diff --git a/.coveragerc b/.coveragerc index 7569b53b..c3140c92 100644 --- a/.coveragerc +++ b/.coveragerc @@ -5,6 +5,5 @@ source = omit = setup.py docs/* - analysis/* venv/* metakb/harvesters/base.py diff --git a/.gitignore b/.gitignore index 1246a916..d996ca72 100644 --- a/.gitignore +++ b/.gitignore @@ -125,8 +125,6 @@ pytest.ini # data files src/metakb/data/* -analysis/graph/*.json -analysis/graph/*.ipynb # Build files Pipfile.lock diff --git a/.travis.yml b/.travis.yml deleted file mode 100644 index a41e43f0..00000000 --- a/.travis.yml +++ /dev/null @@ -1,15 +0,0 @@ -language: python -dist: xenial -python: - - "3.7" -# command to install dependencies -install: - - pip install -r requirements.txt - - pip install -r requirements-dev.txt - - pip install -e . -# command to run tests -script: - - pytest - - flake8 -after_success: - - coveralls diff --git a/EBMetaKB-Python.iml b/EBMetaKB-Python.iml deleted file mode 100644 index db04778c..00000000 --- a/EBMetaKB-Python.iml +++ /dev/null @@ -1,18 +0,0 @@ - - - - - - - - - - - - - - \ No newline at end of file diff --git a/analysis/civic/README.md b/analysis/civic/README.md deleted file mode 100644 index 0030c481..00000000 --- a/analysis/civic/README.md +++ /dev/null @@ -1,10 +0,0 @@ -# CIViC Harvester Analysis - -## `civic_harvester_example.py` -This script creates output examples for the CIViC Harvester. Evidence and variant examples are created from the composite JSON that is made by calling `CIViC().harvest()`. You can find the evidence JSON examples in `analysis/examples`. - -### Evidence Examples -Five evidence examples are created with the evidence item's associated gene and variant. - -### Variant Examples -Examples for BRAF 600E, BCR-ABL, TP53 Loss of Function, and EGFR Amplification are created with only one evidence item being displayed. \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID103.json b/analysis/civic/examples/harvester/EID103.json deleted file mode 100644 index e0399086..00000000 --- a/analysis/civic/examples/harvester/EID103.json +++ /dev/null @@ -1,12070 +0,0 @@ -{ - "EVIDENCE": { - "id": 103, - "name": "EID103", - "description": "V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 110, - "name": "BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis.", - "citation": "Chen et al., 2014, PLoS ONE", - "citation_id": "24594804", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24594804", - "open_access": true, - "pmc_id": "PMC3940924", - "publication_date": { - "year": 2014 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [], - "assertions": [ - { - "id": 20, - "type": "assertion", - "name": "AID20", - "summary": "BRAF V600E indicates poor prognosis in advanced colorectal cancer", - "description": "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers. \nNCCN Guidelines state that that\nmutations in BRAF are a strong prognostic marker, and recommend BRAF genotyping of either primary or metastatic tumor tissue at diagnosis of stage IV disease.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "evidence_type": "Prognostic", - "evidence_direction": "Supports", - "clinical_significance": "Poor Outcome", - "fda_regulatory_approval": false, - "status": "accepted" - } - ], - "gene_id": 5 - }, - "GENE": { - "id": 5, - "name": "BRAF", - "entrez_id": 673, - "description": "BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer.\n\nOncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors.\nClass 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors.\nClass 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors.\nClass 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase.", - "variants": [ - { - "name": "V600E", - "id": 12, - "evidence_items": { - "accepted_count": 88, - "rejected_count": 7, - "submitted_count": 79 - } - }, - { - "name": "T599dup", - "id": 1298, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Mutation", - "id": 399, - "evidence_items": { - "accepted_count": 12, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600_S605delinsDV", - "id": 3241, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600", - "id": 17, - "evidence_items": { - "accepted_count": 22, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E and AMPLIFICATION", - "id": 14, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G496A", - "id": 2221, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "AKAP9-BRAF", - "id": 184, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K483M", - "id": 581, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "intron 10 rearrangement", - "id": 2226, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "CUX1-BRAF", - "id": 2229, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "intron 9 rearrangement", - "id": 2225, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "PAPSS1-BRAF", - "id": 286, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "TRIM24-BRAF", - "id": 287, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "WASFL-BRAF", - "id": 2228, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "AMPLIFICATION", - "id": 1269, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "WILD TYPE", - "id": 426, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "PPFIBP2-BRAF", - "id": 617, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "BRAF-CUL1", - "id": 656, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "MACF1-BRAF", - "id": 2227, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "ZKSCAN1-BRAF", - "id": 657, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "NRF1-BRAF", - "id": 2883, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "APC", - "id": 842, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "N581S", - "id": 1186, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600G", - "id": 1199, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "A728V", - "id": 1198, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K601", - "id": 2765, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L597", - "id": 2766, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "V600L", - "id": 1404, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600M", - "id": 1405, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594", - "id": 2767, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G596", - "id": 2768, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "DELNVTAP", - "id": 1663, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G466A", - "id": 1196, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "AGK-BRAF", - "id": 285, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G469", - "id": 2822, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E/K and AMPLIFICATION", - "id": 2361, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594K", - "id": 2398, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Non-V600", - "id": 2408, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "P731T", - "id": 2224, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G606E", - "id": 2223, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G466V", - "id": 2222, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "DEL 485-490", - "id": 522, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594A", - "id": 579, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594V", - "id": 580, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600K", - "id": 563, - "evidence_items": { - "accepted_count": 8, - "rejected_count": 0, - "submitted_count": 10 - } - }, - { - "name": "L597S", - "id": 582, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K601E", - "id": 584, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "L597V", - "id": 585, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L597Q", - "id": 583, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L505H", - "id": 658, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G596C", - "id": 694, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G469V", - "id": 841, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469A", - "id": 992, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V600R", - "id": 991, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 7 - } - }, - { - "name": "G464V", - "id": 1106, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F595L", - "id": 1121, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469E", - "id": 993, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469R", - "id": 840, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600_K601DELINSD", - "id": 1658, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "G596V", - "id": 1650, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G596R", - "id": 1627, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L597R", - "id": 288, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594N", - "id": 1107, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 5, - "submitted_count": 2 - } - }, - { - "name": "D594G", - "id": 611, - "evidence_items": { - "accepted_count": 9, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EXON 15 MUTATION", - "id": 2650, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "BRAF fusions and mutations", - "id": 2639, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "KIAA1549-BRAF", - "id": 618, - "evidence_items": { - "accepted_count": 11, - "rejected_count": 1, - "submitted_count": 3 - } - }, - { - "name": "FAM131B-BRAF", - "id": 2656, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K439Q", - "id": 2775, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K439T", - "id": 2776, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G466E", - "id": 2792, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L525R", - "id": 2793, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "T488_P492del", - "id": 2795, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P490_Q494del", - "id": 2796, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594E", - "id": 2799, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "class 2 mutations", - "id": 2800, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F247L", - "id": 2802, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R558Q", - "id": 2803, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L485F", - "id": 2804, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600_S602>DT", - "id": 2821, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G593D", - "id": 2823, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V601E", - "id": 2825, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "N486_P490del", - "id": 2794, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V600_K601>E", - "id": 2820, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "A598V", - "id": 2826, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "class 3 mutations", - "id": 2801, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T599_V600insT", - "id": 2824, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "FAM73A-BRAF", - "id": 2987, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594H", - "id": 2832, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E and V600M", - "id": 13, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600D", - "id": 11, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 0 - } - } - ], - "aliases": [ - "BRAF", - "B-raf", - "RAFB1", - "NS7", - "BRAF1", - "B-RAF1" - ], - "type": "gene" - }, - "VARIANT": { - "id": 12, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600E", - "description": "BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 1243.5, - "coordinates": { - "chromosome": "7", - "start": 140453136, - "stop": 140453136, - "reference_bases": "A", - "variant_bases": "T", - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 106, - "name": "EID106", - "description": "BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 112, - "name": "Prognostic value of the BRAF V600E mutation in papillary thyroid carcinoma.", - "citation": "He et al., 2014, Oncol Lett", - "citation_id": "24396464", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24396464", - "open_access": true, - "pmc_id": "PMC3881916", - "publication_date": { - "year": 2014, - "month": 2 - }, - "journal": "Oncol Lett", - "full_journal_title": "Oncology letters", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6123, - "name": "EID6123", - "description": "In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2468, - "name": "Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.", - "citation": "Corcoran et al., 2018, Cancer Discov", - "citation_id": "29431699", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29431699", - "open_access": true, - "pmc_id": "PMC5882509", - "publication_date": { - "year": 2018 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2125, - "name": "EID2125", - "description": "An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 29, - "name": "Mirdametinib", - "ncit_id": "C52195", - "aliases": [ - "PD 901", - "MEK Inhibitor PD0325901", - "PD0325901", - "PD-0325901" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7156, - "name": "EID7156", - "description": "Patients with completely resected colorectal adenocarcinoma (Stage II-III) were treated with fluorouracil and leucovorin +/- ironotecan. Of the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall survival, but not for relapse-free survival, in patients with stages II and III combined, and in stage III alone. For all MSI low and stable tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95% CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40, P=0.0069). The authors note prognostic value for BRAF V600E, especially in non-MSI high tumors.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2783, - "name": "Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.", - "citation": "Roth et al., 2010, J. Clin. Oncol.", - "citation_id": "20008640", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20008640", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 1, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7612, - "name": "EID7612", - "description": "665 patients with BRAF V600E-mutated metastatic CRC were enrolled In this open-label, phase 3 trial. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators\u2019 choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group, 20% in the doublet-therapy group (95% CI 13 to 29) and 2% (95% CI, 0 to 7) in the control group (triplet group vs. control P<0.001). The median overall survival in the triplet-therapy group was 9 months, 8.4 months in the doublet-therapy group and 5.4 months in the control group (hazard ratio for death doublet-group vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 485, - "name": "Binimetinib", - "ncit_id": "C84865", - "aliases": [ - "Mektovi", - "MEK162", - "ARRY-438162", - "ARRY-162" - ] - }, - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 3025, - "name": "Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.", - "citation": "Kopetz et al., 2019, N. Engl. J. Med.", - "citation_id": "31566309", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31566309", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "day": 24 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02928224", - "name": "Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer", - "description": "This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02928224" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8507, - "name": "EID8507", - "description": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Erlotinib and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 142% increased lifespan (ILS) compared to vehicle treated controls. Of ten treated mice, 9 experienced partial response. Doublet therapy produced a greater increase in TGI and ILS than either agent in isolation.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 108, - "name": "Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.", - "citation": "Yang et al., 2012, Cancer Res.", - "citation_id": "22180495", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22180495", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 2, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2135, - "name": "EID2135", - "description": "In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1210, - "name": "Improved survival with MEK inhibition in BRAF-mutated melanoma.", - "citation": "Flaherty et al., 2012, N. Engl. J. Med.", - "citation_id": "22663011", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22663011", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 7, - "day": 12 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01245062", - "name": "GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma", - "description": "This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01245062" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2121, - "name": "EID2121", - "description": "In a study of metastatic colorectal cancer patients treated with capecitabine, oxaliplatin, and bevacizumab, those with BRAF V600E mutations had reduced progression-free survival (5.9mo vs. 12.2mo, P=0.003) and reduced overall survival (15.0mo vs. 24.6mo, P=0.002) compared to those with wildtype BRAF.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 237, - "name": "Oxaliplatin", - "ncit_id": "C1181", - "aliases": [ - "Trans-l Diaminocyclohexane Oxalatoplatinum", - "Trans-l DACH Oxalatoplatinum", - "SR-96669", - "RP-54780", - "RP 54780", - "Oxalatoplatinum", - "Oxalatoplatin", - "Oxalato (trans-l-1,2-diaminocyclohexane)platinum(II)", - "Oxalato (1R,2R-cyclohexanediamine)platinum(II)", - "JM-83", - "Eloxatine", - "ELOXATIN", - "Diaminocyclohexane Oxalatoplatinum", - "DACPLAT", - "Dacotin", - "Aiheng", - "Ai Heng", - "[SP-4-2-(1R-trans)]-(1,2,cyclohexanediamine-N,N')[ethanedioato(2--)-O,O']platinum", - "[(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum", - "1-OHP" - ] - }, - { - "id": 33, - "name": "Bevacizumab", - "ncit_id": "C2039", - "aliases": [ - "Zirabev", - "Mvasi", - "Bevacizumab-bvzr", - "Bevacizumab-awwb", - "Bevacizumab Biosimilar Zirabev", - "Bevacizumab Biosimilar Mvasi", - "Bevacizumab Biosimilar GB-222", - "SCT501", - "RhuMab-VEGF", - "Recombinant Humanized Anti-VEGF Monoclonal Antibody", - "Immunoglobulin G1 (Human-Mouse Monoclonal RhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal RhuMab-VEGF Light Chain, Dimer", - "HD204", - "BP102 Biosimilar", - "BP102", - "Bevacizumab Biosimilar SCT501", - "Bevacizumab Biosimilar RPH-001", - "Bevacizumab Biosimilar QL 1101", - "Bevacizumab Biosimilar MIL60", - "Bevacizumab Biosimilar LY01008", - "Bevacizumab Biosimilar IBI305", - "Bevacizumab Biosimilar HLX04", - "Bevacizumab Biosimilar HD204", - "Bevacizumab Biosimilar FKB238", - "Bevacizumab Biosimilar CT-P16", - "Bevacizumab Biosimilar CBT 124", - "Bevacizumab Biosimilar BI 695502", - "Bevacizumab Biosimilar BEVZ92", - "Bevacizumab Awwb", - "Avastin", - "Anti-VEGF RhuMAb", - "Anti-VEGF Humanized Monoclonal Antibody", - "Anti-VEGF" - ] - }, - { - "id": 32, - "name": "Capecitabine", - "ncit_id": "C1794", - "aliases": [ - "Xeloda", - "Ro 09-1978/000", - "5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1481, - "name": "BRAF mutation in metastatic colorectal cancer.", - "citation": "Tol et al., 2009, N. Engl. J. Med.", - "citation_id": "19571295", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19571295", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 7, - "day": 2 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3771, - "name": "EID3771", - "description": "In a case study, a pediatric grade IV glioblastoma multiforme patient harboring BRAF V600E mutation was associated with a complete response to vemurafenib monotherapy after 4 months of treatment, which was sustained at 6 month of therapy; the patient was undergoing the 7th cycle of therapy at the time of publication of this study.", - "disease": { - "id": 19, - "name": "Glioblastoma", - "display_name": "Glioblastoma", - "doid": "3068", - "url": "http://www.disease-ontology.org/?id=DOID:3068" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1968, - "name": "Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy.", - "citation": "Robinson et al., 2014, BMC Cancer", - "citation_id": "24725538", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24725538", - "open_access": true, - "pmc_id": "PMC3996187", - "publication_date": { - "year": 2014, - "month": 4, - "day": 12 - }, - "journal": "BMC Cancer", - "full_journal_title": "BMC cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2136, - "name": "EID2136", - "description": "Thyroid cancer cell lines with BRAF V600E mutations were more sensitive to the MAPK inhibitor CI-1040 than those with wildtype BRAF (IC50: 0.031-1.251 uM vs. 44.376-278.286 uM). In a mouse xenograft model, the growth of tumors derived from KAT10 cells, which carries the BRAF V600E mutation, was inhibited following treatment with CI-1040 (P<0.01), but drug treatment had no effect on growth of tumors derived from the MRO cell line, which expresses wildtype BRAF.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 462, - "name": "MEK Inhibitor CI-1040", - "ncit_id": "C2670", - "aliases": [ - "PD-184352", - "PD 184352/CI-1040", - "CI-1040", - "2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1493, - "name": "Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations.", - "citation": "Liu et al., 2007, J. Clin. Endocrinol. Metab.", - "citation_id": "17911174", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17911174", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2007, - "month": 12 - }, - "journal": "J. Clin. Endocrinol. Metab.", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 82, - "name": "EID82", - "description": "BRAF status does not predict outcome in patients treated with dacarbazine or temozolomide.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 96, - "name": "BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy.", - "citation": "Meckbach et al., 2014, PLoS ONE", - "citation_id": "24586605", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24586605", - "open_access": true, - "pmc_id": "PMC3930670", - "publication_date": { - "year": 2014 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3781, - "name": "EID3781", - "description": "In a stage IV non-small cell lung cancer patient with a BRAF V600E mutation, who developed adenocarcinoma, BRAF V600E was associated with sensitivity to vemurafenib treatment. The patient was initially treated with four cycles of standard chemotherapy (cisplatin and pemetrexed) and achieved a partial response, subsequently a complete radiologic response was observed with 11 cycle of maintenance chemotherapy. However, the patient\ufffds disease eventually progressed and lung adenocarcinoma and hepatic metastases were observed, the patient received radiotherapy, followed by the administration of vemurafenib monotherapy with concurrent radiotherapy, resulting in an excellent partial response followed by complete response.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1978, - "name": "Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma.", - "citation": "Peters et al., 2013, J. Clin. Oncol.", - "citation_id": "23733758", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23733758", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 7, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2130, - "name": "EID2130", - "description": "An inducible BRAF-V600E mouse melanoma model has shown a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8952, - "name": "EID8952", - "description": "In a preclinical study, Diffuse large B-cell lymphoma cell lines expressing BRAF V600E were resistant to a BCL-2 inhibitor, venetoclax, demonstrating cell growth inhibition at half-maximal growth inhibitory concentration (GI50) larger than 10 \u03bcM when compared to cells expressing vector control (GI50 = 0.43 \u03bcM).", - "disease": { - "id": 45, - "name": "Diffuse Large B-cell Lymphoma", - "display_name": "Diffuse Large B-cell Lymphoma", - "doid": "0050745", - "url": "http://www.disease-ontology.org/?id=DOID:0050745" - }, - "drugs": [ - { - "id": 574, - "name": "Venetoclax", - "ncit_id": "C103147", - "aliases": [ - "Venclyxto", - "Venclexta", - "RG7601", - "GDC-0199", - "ABT199", - "ABT-199", - "ABT-0199", - "4-(4-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3501, - "name": "Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.", - "citation": "Herling et al., 2018, Nat Commun", - "citation_id": "29463802", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29463802", - "open_access": true, - "pmc_id": "PMC5820258", - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "Nat Commun", - "full_journal_title": "Nature communications", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2503, - "name": "EID2503", - "description": "In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001).", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1495, - "name": "The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.", - "citation": "Kim et al., 2012, Cancer", - "citation_id": "21882184", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21882184", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 4, - "day": 1 - }, - "journal": "Cancer", - "full_journal_title": "Cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1408, - "name": "EID1408", - "description": "5 of 7 colorectal cancer (CRC) cell lines with BRAF V600E mutation were resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC line) identified EGFR as an enhancer for survival when exposed to vemurafenib. Treatment with vemurafenib and EGFR inhibitor (cetuximab or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed inhibited growth as well as induction of the cleaved PARP apoptotic marker. WiDr and VACO432 cells were injected into immunodeficient mice. Modest response was seen with vemurafenib treatment, while combination treatment showed considerable tumor growth inhibition as compared to control.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 344, - "name": "Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.", - "citation": "Prahallad et al., 2012, Nature", - "citation_id": "22281684", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22281684", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 3, - "day": 1 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2132, - "name": "EID2132", - "description": "Proposed resistance mechanisms include PDGFRB upregulation or NRAS mutations resulting in MAPK pathway reactivation, but not secondary mutations in BRAF. MEK inhibitors may demonstrate clinical benefit in vemurafenib-resistant melanoma patients.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1491, - "name": "Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.", - "citation": "Nazarian et al., 2010, Nature", - "citation_id": "21107323", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21107323", - "open_access": true, - "pmc_id": "PMC3143360", - "publication_date": { - "year": 2010, - "month": 12, - "day": 16 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 89, - "name": "EID89", - "description": "Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 100, - "name": "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.", - "citation": "Di Nicolantonio et al., 2008, J. Clin. Oncol.", - "citation_id": "19001320", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19001320", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 12, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1749, - "name": "EID1749", - "description": "Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib). Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients (N=37/48). Patients without the V600E mutation had evidence of tumor regression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 352, - "name": "Inhibition of mutated, activated BRAF in metastatic melanoma.", - "citation": "Flaherty et al., 2010, N. Engl. J. Med.", - "citation_id": "20818844", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20818844", - "open_access": true, - "pmc_id": "PMC3724529", - "publication_date": { - "year": 2010, - "month": 8, - "day": 26 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 816, - "name": "EID816", - "description": "This meta-analysis of 7 randomized control trials evaluating overall survival (OS) (8 for progression free survival) could not definitely state that survival benefit of anti-EGFR monoclonal antibodies is limited to patients with wild type BRAF. In other words, the authors believe that there is insufficient data to justify the exclusion of anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In these studies, mutant BRAF specifically meant the V600E mutation.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 548, - "name": "Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.", - "citation": "Rowland et al., 2015, Br. J. Cancer", - "citation_id": "25989278", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25989278", - "open_access": true, - "pmc_id": "PMC4580381", - "publication_date": { - "year": 2015, - "month": 6, - "day": 9 - }, - "journal": "Br. J. Cancer", - "full_journal_title": "British journal of cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3758, - "name": "EID3758", - "description": "In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600E mutation and treated with vemurafenib (n=317) were associated with a 51% response rate, as compared to a 64% response rate (p<0.001) in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=312). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001).", - "disease": { - "id": 206, - "name": "Skin Melanoma", - "display_name": "Skin Melanoma", - "doid": "8923", - "url": "http://www.disease-ontology.org/?id=DOID:8923" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 353, - "name": "Improved overall survival in melanoma with combined dabrafenib and trametinib.", - "citation": "Robert et al., 2015, N. Engl. J. Med.", - "citation_id": "25399551", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25399551", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 1, - "day": 1 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01597908", - "name": "Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma", - "description": "This is a two-arm, open-label, randomised, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to vemurafenib. Subjects with histologically confirmed cutaneous melanoma that is either stage IIIc (unresectable) or stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 694 subjects will be randomised 1:1 (combination therapy:vemurafenib). The primary endpoint is overall survival (OS) for subjects receiving the combination therapy compared with those receiving vemurafenib.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01597908" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3760, - "name": "EID3760", - "description": "Thyroid cancer cell lines with BRAF V600E mutations were more sensitive to vemurafenib than those with wildtype BRAF (IC50: 0.115\ufffd 1.156 uM vs. 56.674\ufffd1349.788 uM).", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1959, - "name": "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells.", - "citation": "Sala et al., 2008, Mol. Cancer Res.", - "citation_id": "18458053", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18458053", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 5 - }, - "journal": "Mol. Cancer Res.", - "full_journal_title": "Molecular cancer research : MCR", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2118, - "name": "EID2118", - "description": "The presence of BRAF V600E or D594K was associated with reduced progression-free survival in 5 patients with metastatic colorectal cancer treated with irinotecan-based first line therapy (3.5mo vs. 12.8mo, HR:4.1, 95%CI:1.5-11.3, P=0.006) when compared to 39 patients with wildtype BRAF.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1479, - "name": "Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.", - "citation": "Souglakos et al., 2009, Br. J. Cancer", - "citation_id": "19603024", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19603024", - "open_access": true, - "pmc_id": "PMC2720232", - "publication_date": { - "year": 2009, - "month": 8, - "day": 4 - }, - "journal": "Br. J. Cancer", - "full_journal_title": "British journal of cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2115, - "name": "EID2115", - "description": "In metastatic colorectal cancer patients with wildtype KRAS status, those with a BRAF V600E mutation were less likely to respond to treatment with cetuximab or panitumumab than those with wildtype BRAF (0% vs. 32% , P=0.029). Regardless of KRAS status, patients with BRAF mutations had reduced progression-free and overall survival (P=0.0107 and P <0.0001, respectively). Transfection of the colorectal cancer cell line DiFi with a BRAF V600E expression vector conferred decreased sensitivity to cetuximab and panitumumab in comparison to cells transfected with empty vector.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 100, - "name": "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.", - "citation": "Di Nicolantonio et al., 2008, J. Clin. Oncol.", - "citation_id": "19001320", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19001320", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 12, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7077, - "name": "EID7077", - "description": "The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 617, - "name": "Dual IGF-1R/InsR Inhibitor BMS-754807", - "ncit_id": "C74043", - "aliases": [ - "BMS-754807" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 2752, - "name": "IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.", - "citation": "Huang et al., 2015, Mol. Cancer Ther.", - "citation_id": "25527633", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25527633", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 2 - }, - "journal": "Mol. Cancer Ther.", - "full_journal_title": "Molecular cancer therapeutics", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7191, - "name": "EID7191", - "description": "Using Sanger sequencing, BRAFV600E mutations were identified in 21 of 285 patients with PLGGs (7.4%). This mutation was enriched in hemispheric tumors (p<0.007) and was associated with shorter progression-free survival (p=0.011) and overall survival (p=0.032) [mt (n=18) vs wt (n=166)].", - "disease": { - "id": 3048, - "name": "Pediatric Low-grade Glioma", - "display_name": "Pediatric Low-grade Glioma", - "doid": "0080830", - "url": "http://www.disease-ontology.org/?id=DOID:0080830" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2816, - "name": "Pediatric low-grade gliomas can be molecularly stratified for risk.", - "citation": "Yang et al., 2018, Acta Neuropathol.", - "citation_id": "29948154", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29948154", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018 - }, - "journal": "Acta Neuropathol.", - "full_journal_title": "Acta neuropathologica", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 9170, - "name": "EID9170", - "description": "Clinical study including 219 patients with papillary thyroid cancer (PTC) to determine a correlation between the BRAF V600E mutation and poor oncological outcome. This study found that 107 of the 219 (49%) patients had this mutation signifying that the BRAF V600E mutation is one of the most commonly occurring among PTC patients. This cohort was split into two groups\u2014BRAF+ and BRAF-. Of the 107 patients that were BRAF+, 25% had tumor reoccurrence compared with 9% in the BRAF- group (P=0.004). Multivariate analysis was performed to assess BRAF correlation independent of known contributing factors to cancer such as age, gender, and multifocality. The results showed that the BRAF mutation is indicative/contributes to lymph node metastasis, associated with tumor reoccurrence, stage, and that recurrent disease was more extensive and required more aggressive treatments in BRAF+ patients compared with BRAF- patients. The authors conclude that PTC patients with the BRAF V600E mutation have worse clinicopathological outcomes, and that the BRAF mutation can be used to assess risk stratification in patients with PTC.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 3893, - "name": "BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.", - "citation": "Xing et al., 2005, J Clin Endocrinol Metab", - "citation_id": "16174717", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16174717", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2005, - "month": 12 - }, - "journal": "J Clin Endocrinol Metab", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 98, - "name": "EID98", - "description": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Capecitabine, bevacizumab and vemurafenib combination therapy resulted in 100% tumor growth inhibition (TGI) and 190% increased lifespan (ILS) compared to vehicle treated controls. Seven mice experienced partial response and two experienced complete response. Triplet therapy resulted in better TGI and ILS compared to any agent in isolation or capecitabine + vemurafenib doublet therapy (p <0.05, p <0.0001, for all comparisons).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 33, - "name": "Bevacizumab", - "ncit_id": "C2039", - "aliases": [ - "Zirabev", - "Mvasi", - "Bevacizumab-bvzr", - "Bevacizumab-awwb", - "Bevacizumab Biosimilar Zirabev", - "Bevacizumab Biosimilar Mvasi", - "Bevacizumab Biosimilar GB-222", - "SCT501", - "RhuMab-VEGF", - "Recombinant Humanized Anti-VEGF Monoclonal Antibody", - "Immunoglobulin G1 (Human-Mouse Monoclonal RhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal RhuMab-VEGF Light Chain, Dimer", - "HD204", - "BP102 Biosimilar", - "BP102", - "Bevacizumab Biosimilar SCT501", - "Bevacizumab Biosimilar RPH-001", - "Bevacizumab Biosimilar QL 1101", - "Bevacizumab Biosimilar MIL60", - "Bevacizumab Biosimilar LY01008", - "Bevacizumab Biosimilar IBI305", - "Bevacizumab Biosimilar HLX04", - "Bevacizumab Biosimilar HD204", - "Bevacizumab Biosimilar FKB238", - "Bevacizumab Biosimilar CT-P16", - "Bevacizumab Biosimilar CBT 124", - "Bevacizumab Biosimilar BI 695502", - "Bevacizumab Biosimilar BEVZ92", - "Bevacizumab Awwb", - "Avastin", - "Anti-VEGF RhuMAb", - "Anti-VEGF Humanized Monoclonal Antibody", - "Anti-VEGF" - ] - }, - { - "id": 32, - "name": "Capecitabine", - "ncit_id": "C1794", - "aliases": [ - "Xeloda", - "Ro 09-1978/000", - "5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 108, - "name": "Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.", - "citation": "Yang et al., 2012, Cancer Res.", - "citation_id": "22180495", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22180495", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 2, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5960, - "name": "EID5960", - "description": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients with BRAF V600E mutant colorectal cancer, 1 had a partial response.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2414, - "name": "Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.", - "citation": "Hainsworth et al., 2018, J. Clin. Oncol.", - "citation_id": "29320312", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29320312", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02091141", - "name": "My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors", - "description": "This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02091141" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2133, - "name": "EID2133", - "description": "Acquired resistance to vemurafenib in BRAF-V600E positive melanomas frequently confound vemurafenib therapy.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1492, - "name": "COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.", - "citation": "Johannessen et al., 2010, Nature", - "citation_id": "21107320", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21107320", - "open_access": true, - "pmc_id": "PMC3058384", - "publication_date": { - "year": 2010, - "month": 12, - "day": 16 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7583, - "name": "EID7583", - "description": "Off-label use of vemurafenib to treat BRAF V600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.\nFifty-four patients from 12 countries were treated with vemurafenib 20 mg/kg/day.\nBecause LCH is a heterogeneous systemic disease, the quantitative Disease Activity Score (DAS), which reflects overall LCH extension, was used as an evaluation criterion.\nAt 8 weeks, 38 patients had CRs (non-active disease) and 16 PRs (active disease better).", - "disease": { - "id": 1762, - "name": "Langerhans Cell Sarcoma", - "display_name": "Langerhans Cell Sarcoma", - "doid": "7146", - "url": "http://www.disease-ontology.org/?id=DOID:7146" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3012, - "name": "Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.", - "citation": "Donadieu et al., 2019, J. Clin. Oncol.", - "citation_id": "31513482", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31513482", - "open_access": true, - "pmc_id": "PMC6823889", - "publication_date": { - "year": 2019, - "month": 11, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2145, - "name": "EID2145", - "description": "In a study of pediatric low-grade gliomas, BRAF V600E mutation was associated with a strong trend toward reduced progression free survival (HR:2.39, 95%CI:0.93-6.15, P=0.07, multivariate analysis).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1499, - "name": "Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.", - "citation": "Horbinski et al., 2012, Neuro-oncology", - "citation_id": "22492957", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22492957", - "open_access": true, - "pmc_id": "PMC3367847", - "publication_date": { - "year": 2012, - "month": 6 - }, - "journal": "Neuro-oncology", - "full_journal_title": "Neuro-oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 104, - "name": "EID104", - "description": "BRAF V600E is correlated with shorter disease-free and overall Survival in a Spanish cohort of melanoma patients.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 111, - "name": "Prognostic value of BRAF mutations in localized cutaneous melanoma.", - "citation": "Nagore et al., 2014, J. Am. Acad. Dermatol.", - "citation_id": "24388723", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24388723", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 5 - }, - "journal": "J. Am. Acad. Dermatol.", - "full_journal_title": "Journal of the American Academy of Dermatology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 102, - "name": "EID102", - "description": "Unlike other studies that suggest a poorer outcome, BRAF mutation in this study was not correlated with poorer prognosis in papillary thyroid cancer.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 109, - "name": "The BRAF(V600E) mutation in papillary thyroid microcarcinoma: does the mutation have an impact on clinical outcome?", - "citation": "Walczyk et al., 2014, Clin. Endocrinol. (Oxf)", - "citation_id": "24354346", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24354346", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 6 - }, - "journal": "Clin. Endocrinol. (Oxf)", - "full_journal_title": "Clinical endocrinology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2119, - "name": "EID2119", - "description": "Among metastatic colorectal cancer patients treated with cetuximab and irinotecan, those with BRAF V600E mutations were less likely to achieve a complete or partial response to therapy (0% , P=0.016, Fisher\ufffds exact test) and had reduced median overall survival (4.1mo vs. 13.9mo, HR:0.51, 95%CI:0.18-0.95, P=0.037) than patients with wildtype BRAF.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1480, - "name": "KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer.", - "citation": "Loupakis et al., 2009, Br. J. Cancer", - "citation_id": "19603018", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19603018", - "open_access": true, - "pmc_id": "PMC2736831", - "publication_date": { - "year": 2009, - "month": 8, - "day": 18 - }, - "journal": "Br. J. Cancer", - "full_journal_title": "British journal of cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3768, - "name": "EID3768", - "description": "In a hairy cell leukemia patient harboring BRAF V600E mutation, BRAF V600E mutation was associated with improved response to vemurafenib treatment. The patient was treated with 3 lines of chemotherapy, including 6 cycles of pentostatin and rituximab combination therapy, but experience progressive disease; subsequently, the patient was treated with vemurafenib monotherapy for 58 days and achieved a partial response.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1965, - "name": "Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to low dose vemurafenib.", - "citation": "Follows et al., 2013, Br. J. Haematol.", - "citation_id": "23278307", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23278307", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 4 - }, - "journal": "Br. J. Haematol.", - "full_journal_title": "British journal of haematology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2894, - "name": "EID2894", - "description": "Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 100, - "name": "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.", - "citation": "Di Nicolantonio et al., 2008, J. Clin. Oncol.", - "citation_id": "19001320", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19001320", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 12, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1902, - "name": "EID1902", - "description": "Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable patients achieved an objective response, 15 patients total had either stable disease or radiographic response (the patient with appendiceal cancer had disease progression). Estimated median PFS was 7.7 months. Effect of the combined treatment was also observed in xenograft and cell line studies.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1336, - "name": "Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.", - "citation": "Hong et al., 2016, Cancer Discov", - "citation_id": "27729313", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27729313", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 12 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01787500", - "name": "Vemurafenib, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or That Cannot Be Removed by Surgery", - "description": "This phase I trial studies the side effects and best dose of vemurafenib when given together with cetuximab and irinotecan hydrochloride in treating patients with solid tumors that have spread to other parts of the body or cannot be removed by surgery. Vemurafenib and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vemurafenib with cetuximab and irinotecan hydrochloride may be a better treatment for solid tumors.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01787500" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1428, - "name": "EID1428", - "description": "In a mouse model of BRAF V600E colorectal cancer, western blots from tumors in mice treated with BRAF inhibitor GDC-0879 and PI3K/mTOR inhibitor BEZ235 showed stronger reduction in phospho-Akt and phospho-S6 than PI3K/mTOR inhibitor alone, and combination inhibition also resulted in stronger phospho-ERK inhibition in tumors than did BRAF inhibition alone. Increased apoptosis in tumors was seen in dual treatment conditions with increased TUNEL-positive cells. In vehicle treated mice, area of colon covered by tumor increased, while treatment with single agent inhibitors caused growth inhibition resulting in no change in colon area covered by tumors. Administration of dual inhibitors induced tumor regression apparent in a decrease of colonic area covered by tumors over the course of treatment.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 344, - "name": "GDC-0879", - "ncit_id": null, - "aliases": [] - }, - { - "id": 343, - "name": "Dactolisib", - "ncit_id": "C74072", - "aliases": [ - "NVPBEZ235", - "BEZ235", - "Benzeneacetonitrile, 4-(2,3-Dihydro-3-methyl-2-oxo-8-(3-quinolinyl)-1H-imidazo(4,5-c)quinolin-1-yl)-alpha,alpha-dimethyl-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 967, - "name": "Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer.", - "citation": "Coffee et al., 2013, Clin. Cancer Res.", - "citation_id": "23549875", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23549875", - "open_access": true, - "pmc_id": "PMC3815598", - "publication_date": { - "year": 2013, - "month": 5, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3775, - "name": "EID3775", - "description": "In an in vitro study, K2, a papillary thyroid carcinoma cell line expressing the BRAFV600E mutation, was associated with sensitivity to dasatinib treatment. Sensitivity was determined by assessing cell growth inhibition. In an in vivo experiment, dasatinib also inhibited the growth of K2 thyroid carcinoma xenografts in 7 of 13 mice.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 20, - "name": "Dasatinib", - "ncit_id": "C38713", - "aliases": [ - "Sprycel", - "Dasatinib Monohydrate", - "Dasatinib Hydrate", - "BMS-354825", - "5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-, Monohydrate" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1972, - "name": "Src inhibitors in suppression of papillary thyroid carcinoma growth.", - "citation": "Henderson et al., 2014, Head Neck", - "citation_id": "23729178", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23729178", - "open_access": true, - "pmc_id": "PMC4401074", - "publication_date": { - "year": 2014, - "month": 3 - }, - "journal": "Head Neck", - "full_journal_title": "Head & neck", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5961, - "name": "EID5961", - "description": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant anaplastic thyroid cancer had a complete response.", - "disease": { - "id": 3040, - "name": "Thyroid Gland Anaplastic Carcinoma", - "display_name": "Thyroid Gland Anaplastic Carcinoma", - "doid": "0080522", - "url": "http://www.disease-ontology.org/?id=DOID:0080522" - }, - "drugs": [ - { - "id": 247, - "name": "Pertuzumab", - "ncit_id": "C38692", - "aliases": [ - "RO4368451", - "RhuMAb2C4", - "Perjeta", - "Omnitarg", - "Monoclonal Antibody 2C4", - "MoAb 2C4", - "Immunoglobulin G1, Anti-(Human V (Receptor)) (Human-Mouse Monoclonal 2C4 Heavy Chain), Disulfide With Human-Mouse Monoclonal 2C4 Kappa-Chain, Dimer", - "2C4 Antibody", - "2C4" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2414, - "name": "Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.", - "citation": "Hainsworth et al., 2018, J. Clin. Oncol.", - "citation_id": "29320312", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29320312", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02091141", - "name": "My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors", - "description": "This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02091141" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1414, - "name": "EID1414", - "description": "A 73 year old patient with prior history of breast cancer presented with metastatic papillary thyroid carcinoma. After two treatments of I-131 a comprehensive tumor profile revealed BRAF V600E as the only genetic alteration on a near diploid genome with trisomy 1q. Vemurafenib treatment resulted in improvement of symptoms and considerable reductions in tumor mass, and after 23 months the patient remained on therapy with well controlled disease.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 958, - "name": "Extended Antitumor Response of a BRAF V600E Papillary Thyroid Carcinoma to Vemurafenib.", - "citation": "Ali et al., 2014, Case Rep Oncol", - "citation_id": "24987354", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24987354", - "open_access": true, - "pmc_id": "PMC4067722", - "publication_date": { - "year": 2014, - "month": 5 - }, - "journal": "Case Rep Oncol", - "full_journal_title": "Case reports in oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1141, - "name": "EID1141", - "description": "Preclinical study analyzing the differential response to MEK inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours. This study provides mechanistic rationale for improved efficacy of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting through an alternative mechanism (GDC-0623 and G-573).", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 790, - "name": "Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.", - "citation": "Hatzivassiliou et al., 2013, Nature", - "citation_id": "23934108", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23934108", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 9, - "day": 12 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1699, - "name": "EID1699", - "description": "A 54-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and received an autologous stem cell transplant. Genomic profiling of the bone biopsy revealed BRAF V600E activating mutation and the patient was treated with vemurafenib. At 4-months post treatment (time of case study report) the patient maintains near-resolution of hypermetabolic lesions.", - "disease": { - "id": 41, - "name": "Multiple Myeloma", - "display_name": "Multiple Myeloma", - "doid": "9538", - "url": "http://www.disease-ontology.org/?id=DOID:9538" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1147, - "name": "Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma.", - "citation": "Sharman et al., 2014, Clin Lymphoma Myeloma Leuk", - "citation_id": "24997557", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24997557", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 10 - }, - "journal": "Clin Lymphoma Myeloma Leuk", - "full_journal_title": "Clinical lymphoma, myeloma & leukemia", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2140, - "name": "EID2140", - "description": "In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001).", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 463, - "name": "RDEA 119", - "ncit_id": null, - "aliases": [] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1495, - "name": "The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.", - "citation": "Kim et al., 2012, Cancer", - "citation_id": "21882184", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21882184", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 4, - "day": 1 - }, - "journal": "Cancer", - "full_journal_title": "Cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 91, - "name": "EID91", - "description": "In a patient with V600E-positive NSCLC, KRAS G12D seemed to confer resistance to dabrafenib.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 101, - "name": "Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer.", - "citation": "Rudin et al., 2013, J Thorac Oncol", - "citation_id": "23524406", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23524406", - "open_access": true, - "pmc_id": "PMC3634121", - "publication_date": { - "year": 2013, - "month": 5 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2138, - "name": "EID2138", - "description": "In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001).", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 462, - "name": "MEK Inhibitor CI-1040", - "ncit_id": "C2670", - "aliases": [ - "PD-184352", - "PD 184352/CI-1040", - "CI-1040", - "2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1495, - "name": "The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.", - "citation": "Kim et al., 2012, Cancer", - "citation_id": "21882184", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21882184", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 4, - "day": 1 - }, - "journal": "Cancer", - "full_journal_title": "Cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1698, - "name": "EID1698", - "description": "A 65-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and he received an autologous stem cell transplant. Sequencing of the recurrent tumor harbored BRAF V600E mutation and he was treated with vemurafenib. After 7 weeks of treatment, the patient relapsed and died.", - "disease": { - "id": 41, - "name": "Multiple Myeloma", - "display_name": "Multiple Myeloma", - "doid": "9538", - "url": "http://www.disease-ontology.org/?id=DOID:9538" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1147, - "name": "Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma.", - "citation": "Sharman et al., 2014, Clin Lymphoma Myeloma Leuk", - "citation_id": "24997557", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24997557", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 10 - }, - "journal": "Clin Lymphoma Myeloma Leuk", - "full_journal_title": "Clinical lymphoma, myeloma & leukemia", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7157, - "name": "EID7157", - "description": "The CRYSTAL Phase III Trial evaluated efficacy of irinotecan, fluorouracil, and leucovorin (FOLFIRI) with or without Cetuximab for colorectal cancer patients who presented with unresectable metastatic disease. BRAF mutation status (V600E) was analyzed via LightMix BRAF V600E Kit. V600E mutations were detected in 60/999 tumor samples (6%), 59 of which were wild-type for KRAS. When comparing patients with wildtype KRAS (n=625), BRAF V600E tumors had worse outcomes relative to BRAF wildtype. For patients with BRAF V600E tumors (n=566), median overall survival (OS) was 25.1 months with cetuximab and 21.6 months without cetuximab. For patients with wildtype BRAF (n=59), median OS was 14.1 months with cetuximab and 10.3 months without cetuximab.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1931, - "name": "Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.", - "citation": "Van Cutsem et al., 2011, J. Clin. Oncol.", - "citation_id": "21502544", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21502544", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 5, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3749, - "name": "EID3749", - "description": "In a retrospective study of 30 metastatic melanoma patients with progressing metastases, patients with BRAF V600E mutation (n=8) treated with vemurafenib monotherapy achieved a partial response (n=5) and stable disease (n=1).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1951, - "name": "BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact.", - "citation": "Rizos et al., 2014, Clin. Cancer Res.", - "citation_id": "24463458", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24463458", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 4, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 994, - "name": "EID994", - "description": "This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 17 patients with BRAF V600E melanoma, 4 achieved partial response, 5 experienced stable disease lasting longer than 16 weeks, and 8 experienced disease progression (including 2 with prior vemurafenib treatment). One of the partial responders had a concomitant EGFR mutation, and two of the stable disease patients had other concomitant mutations (in RET or MET). The median days on treatment was 113 (18-366) for BRAF V600E melanoma patients and 107 (17-323) for BRAF V600 wildtype patients (n=23). Patients with BRAF V600E mutant melanoma experienced similar response rates (24% vs 20%) and rates of metabolic response measured by decrease in FDG uptake assessed by FDG-PET (86% vs 75%) compared to non-BRAF mutant patients. Patients with melanoma, either BRAF wt or V600E, experienced significant decreases in Ki67 expression by day 15 of MEK inhibitor treatment (P<0.02). The authors conclude that RO4987655 has clinical activity in BRAF V600E and BRAF wt melanoma.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 243, - "name": "MEK Inhibitor RO4987655", - "ncit_id": "C82696", - "aliases": [ - "RO4987655" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 688, - "name": "Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations.", - "citation": "Zimmer et al., 2014, Clin. Cancer Res.", - "citation_id": "24947927", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24947927", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 8, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 656, - "name": "EID656", - "description": "In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T (N=35), recurrence-free survival is worse than in patients harboring one of these mutations (N=159 BRAF, N=26 TERT promoter mutated) or no mutations in either gene (N=287)(P<0.001).", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 413, - "name": "BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence.", - "citation": "Xing et al., 2014, J. Clin. Oncol.", - "citation_id": "25024077", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25024077", - "open_access": true, - "pmc_id": "PMC4145183", - "publication_date": { - "year": 2014, - "month": 9, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 96, - "name": "EID96", - "description": "Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720 administration to NSG mice subcutanousely injected with colorectal cell lines with a BRAF V600E mutation effectively inhibited tumor growth and reduced cellular proliferation.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 477, - "name": "Pictilisib Bismesylate", - "ncit_id": "C82380", - "aliases": [ - "Thieno(3,2-d)pyrimidine, 2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl)methyl)-4-(4-morpholinyl)-, Methanesulfonate (1:2)", - "Pictilisib Dimesylate", - "GDC-0941 Dimesylate", - "GDC-0941 Bismesylate", - "2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- Ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, Bimesylate Salt" - ] - }, - { - "id": 30, - "name": "PLX4720", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 106, - "name": "A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.", - "citation": "Rad et al., 2013, Cancer Cell", - "citation_id": "23845441", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23845441", - "open_access": true, - "pmc_id": "PMC3706745", - "publication_date": { - "year": 2013, - "month": 7, - "day": 8 - }, - "journal": "Cancer Cell", - "full_journal_title": "Cancer cell", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3784, - "name": "EID3784", - "description": "In an in vitro study, BRAF V600E expressing cell lines (BCPAP, OCUT1, K1 and SW1736) demonstrated increased sensitivity to vemurafenib treatment, compared to BRAF wild-type expressing cells (FTC133, KAT18, Hth74 and WRO). Sensitivity was determined by assessing cell proliferation (OCUT1, IC50: 0.41uM; SW1736, IC50: 0.12 uM; K1, IC50: 0.83 uM; BCPAP, IC50: 1.16 uM vs. FTC133, IC50: 56.67 uM; KAT18, 541.66 uM; Hth74, IC50: 1349.79 uM; and WRO IC50: 943.73 uM) and ERK phosphorylation.", - "disease": { - "id": 155, - "name": "Thyroid Gland Carcinoma", - "display_name": "Thyroid Gland Carcinoma", - "doid": "3963", - "url": "http://www.disease-ontology.org/?id=DOID:3963" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1981, - "name": "The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204).", - "citation": "Xing et al., 2011, Biochem. Biophys. Res. Commun.", - "citation_id": "21185263", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21185263", - "open_access": true, - "pmc_id": "PMC4596240", - "publication_date": { - "year": 2011, - "month": 1, - "day": 28 - }, - "journal": "Biochem. Biophys. Res. Commun.", - "full_journal_title": "Biochemical and biophysical research communications", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 107, - "name": "EID107", - "description": "V600E is correlated with disease recurrence in both age cohorts (>65 and <65 yo).", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 93, - "name": "Both BRAF V600E mutation and older age (\u2265 65 years) are associated with recurrent papillary thyroid cancer.", - "citation": "Howell et al., 2011, Ann. Surg. Oncol.", - "citation_id": "21594703", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21594703", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 12 - }, - "journal": "Ann. Surg. Oncol.", - "full_journal_title": "Annals of surgical oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5904, - "name": "EID5904", - "description": "Dabrafenib and trametinib combination showed durable response for patients with standard chemotherapy refractory cholangiocarcinoma havoring BRAF V600E.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 548, - "name": "Trametinib Dimethyl Sulfoxide", - "ncit_id": "C152711", - "aliases": [ - "Mekinist" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2379, - "name": "Dramatic response to dabrafenib and trametinib combination in a BRAF V600E-mutated cholangiocarcinoma: implementation of a molecular tumour board and next-generation sequencing for personalized medicine.", - "citation": "Loaiza-Bonilla et al., 2014, Ecancermedicalscience", - "citation_id": "25435907", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25435907", - "open_access": true, - "pmc_id": "PMC4239128", - "publication_date": { - "year": 2014 - }, - "journal": "Ecancermedicalscience", - "full_journal_title": "Ecancermedicalscience", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1405, - "name": "EID1405", - "description": "In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF V600E, one patient had a durable 21 week partial response, and seven patients had 8 week stable disease as best response. Median progression free survival was 2.1 months and median overall survival was 7.7 months. The authors conclude that single agent vemurafenib did not show meaningful activity in V600E CRC, in contrast to the significant vemurafenib activity against V600 in melanoma.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 953, - "name": "Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.", - "citation": "Kopetz et al., 2015, J. Clin. Oncol.", - "citation_id": "26460303", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26460303", - "open_access": true, - "pmc_id": "PMC4669589", - "publication_date": { - "year": 2015, - "month": 12, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00405587", - "name": "Safety Study of PLX4032 in Patients With Solid Tumors", - "description": "The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00405587" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3738, - "name": "EID3738", - "description": "In a retrospective study of 68 irinotecan-refractory metastatic colorectal cancer patients, the tumors of eight patients harbored BRAF V600E but were wildtype for KRAS codons 12, 13, 61 and 146 mutations. None of these patients responded to irinotecan and cetuximab combination therapy. Conversely, 22/60 (37%) patients with BRAF wildtype type disease responded (p = 0.047). Authors note that BRAF V600E was associated with a trend toward shorter progression free survival (PFS) and overall survival (OS) compared to patients whose tumors had same KRAS genotype but were wildtype for BRAF though the trend had not reached significance (median PFS: 3.9 vs 5.3 mo, p = 0.306; median OS 9.0 vs 14.8 mo, p = 0.279).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 1480, - "name": "KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer.", - "citation": "Loupakis et al., 2009, Br. J. Cancer", - "citation_id": "19603018", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19603018", - "open_access": true, - "pmc_id": "PMC2736831", - "publication_date": { - "year": 2009, - "month": 8, - "day": 18 - }, - "journal": "Br. J. Cancer", - "full_journal_title": "British journal of cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3779, - "name": "EID3779", - "description": "In a case report, a clear cell sarcoma patient harboring BRAF V600E mutation with distant metastases was associated with a complete response to vemurafenib monotherapy at 8 weeks of treatment. Prior to the administration of vemurafenib, the patient had undergone surgery and was treated with radiation, and standard chemotherapy, but had developed progressive disease.", - "disease": { - "id": 966, - "name": "Clear Cell Sarcoma", - "display_name": "Clear Cell Sarcoma", - "doid": "4233", - "url": "http://www.disease-ontology.org/?id=DOID:4233" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1976, - "name": "BRAF-mutated clear cell sarcoma is sensitive to vemurafenib treatment.", - "citation": "Protsenko et al., 2015, Invest New Drugs", - "citation_id": "26286452", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26286452", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 10 - }, - "journal": "Invest New Drugs", - "full_journal_title": "Investigational new drugs", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2124, - "name": "EID2124", - "description": "In a mouse in vivo study of MEK protein inhibitor, PD-0325901, was able to suppress growth of SKMEL28 BRAF-V600E xenograft tumors (P<0.01). The reduction of growth was associated with loss of D-cyclin expression and induction of p27.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 29, - "name": "Mirdametinib", - "ncit_id": "C52195", - "aliases": [ - "PD 901", - "MEK Inhibitor PD0325901", - "PD0325901", - "PD-0325901" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1487, - "name": "BRAF mutation predicts sensitivity to MEK inhibition.", - "citation": "Solit et al., 2006, Nature", - "citation_id": "16273091", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16273091", - "open_access": true, - "pmc_id": "PMC3306236", - "publication_date": { - "year": 2006, - "month": 1, - "day": 19 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 9018, - "name": "EID9018", - "description": "Open label phase 2 (Clinical Level B) trial including patients from across the globe (USA, Italy, and the Netherlands) investigating sensitivity to Vemurafenib in patients that have BRAF V600E-positive papillary thyroid cancer that have become resistant to radioactive iodine (the standard treatment). There were 116 patients identified for this trial, 51 of which met the conditions to be included. These 51 patients were split into two cohorts: 1) patients that had never been treated with a multikinase inhibitor targeting VEGFR and 2) patients that have previously been treated with a VEGFR multikinase inhibitor. In cohort 1, ten of 26 patients had best overall response. Best overall response was defined as the proportion of patients with a complete or partial response, however these ten patients were all partial response. In the same cohort 1, nine had achieved stable disease control for at least six months; therefore, 19 patients achieved disease control (73% of total cohort 1, 95% CI 52-88). In cohort 2, of 23 eligible patients, six had a partial response as best overall response and six had stable disease control for at least six months; therefore, 12 patients achieved disease control. (55% of total cohort 2, 95% CI 32-76). The authors conclude that vemurafenib is a potential treatment option for late-stage BRAF V600E-positive papillary thyroid cancer for treatment in patients na\u00efve to a multikinase inhibitor (Cohort 1) and to patients that have been previously treated with a multikinase inhibitor (Cohort 2).", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1052, - "name": "Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.", - "citation": "Brose et al., 2016, Lancet Oncol.", - "citation_id": "27460442", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27460442", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 7, - "day": 22 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01286753", - "name": "A Study of Vemurafenib (RO5185426) in Participants With Metastatic or Unresectable Papillary Thyroid Cancer Positive for the BRAF V600 Mutation", - "description": "This open-label, multi-center study will evaluate the safety and efficacy of Vemurafenib (RO5185426) in participants with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine therapy. Participants will receive vemurafenib 960 milligrams (mg) orally twice daily until progressive disease or unacceptable toxicity occurs.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01286753" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2362, - "name": "EID2362", - "description": "This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was identified in 5 cases. The authors reported that no differences were found in overall survival between patients with and without BRAF mutations (P > 0.1).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1475, - "name": "PIK3CA mutations predict local recurrences in rectal cancer patients.", - "citation": "He et al., 2009, Clin. Cancer Res.", - "citation_id": "19903786", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19903786", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 11, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1552, - "name": "EID1552", - "description": "In a study of 908 patients with colorectal cancer, 45 patients had BRAF V600E mutations and 589 patients were BRAF wild type. BRAF V600E mutations were more likely to be proximal tumors (68.9%, 20.7%; p<0.0001), they were more likely to be poorly differentiated (17.7%, 1.9%; p<0.0001), they were more likely to be mucinous carcinoma type (20.0%, 4.2%; p=0.0003), they were more likely to have lymphatic invasion (77.6%, 49.9%; p=0.0003), and they had a shorter survival time (31.1 mo, 41.6 mo; p=0.001). The 3-year survival rate was significantly poorer in the V600E group when compared to the wild type group (63.8%, 87.9%; p<0.0001).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1027, - "name": "Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis.", - "citation": "Amaki-Takao et al., 2016, Oncology", - "citation_id": "27404270", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27404270", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 7, - "day": 13 - }, - "journal": "Oncology", - "full_journal_title": "Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3017, - "name": "EID3017", - "description": "Patients with BRAF V600E-mutant NSCLC (n=57) were enrolled into a phase 2, multicentre, non-randomised, open-label study, administering dabrafenib plus trametinib. The overall response rate was 36/57 (63.2%, [95% CI 49.3-75.6]) and the median progression-free survival was 9.7 months (95% CI 6.9-19.6). At data cutoff (11.6 months of follow-up), 18/36 (50%) confirmed responses were ongoing and 23/57 (40%) of patients had died.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1296, - "name": "Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.", - "citation": "Planchard et al., 2016, Lancet Oncol.", - "citation_id": "27283860", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27283860", - "open_access": true, - "pmc_id": "PMC4993103", - "publication_date": { - "year": 2016, - "month": 7 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01336634", - "name": "Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.", - "description": "Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg twice daily (BID) in monotherapy treatment and dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01336634" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3782, - "name": "EID3782", - "description": "In a retrospective study of 35 lung adenocarcinoma patients (with chemotherapy previously administered in 86% of patients), patients harboring a BRAF V600E mutation and treated with vemurafenib monotherapy (n=29) were associated with an improved response rate; an overall survival (with 1st-line therapy) of 25.63 months, a 54% overall response rate and a 95% disease control rate were reported.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1979, - "name": "Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort.", - "citation": "Gautschi et al., 2015, J Thorac Oncol", - "citation_id": "26200454", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26200454", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 10 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3777, - "name": "EID3777", - "description": "In a case report, a 28 month old patient with a cervicomedullary low grade glioma compatible with pilocytic astrocytoma which was resected had a second lesion consistent with a ganglioglioma 3 years later. This mass progressed under treatment at which point PCR amplification of BRAF exon 15 and subsequent Sanger sequencing the initial biopsy revealed the tumor harbored a BRAF V600E mutation. Based on these results, vemurafenib monotherapy was started and radiological and clinical response was noted after 3 months of treatment, which was sustained after 6 months of therapy. Prior to vemurafenib treatment, the patient had undergone tracheotomy, was treated with standard chemotherapy and underwent another surgery, but had developed progressive disease.", - "disease": { - "id": 1673, - "name": "Childhood Pilocytic Astrocytoma", - "display_name": "Childhood Pilocytic Astrocytoma", - "doid": "6812", - "url": "http://www.disease-ontology.org/?id=DOID:6812" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1974, - "name": "Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent.", - "citation": "del Bufalo et al., 2014, J Transl Med", - "citation_id": "25524464", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25524464", - "open_access": true, - "pmc_id": "PMC4279809", - "publication_date": { - "year": 2014, - "month": 12, - "day": 19 - }, - "journal": "J Transl Med", - "full_journal_title": "Journal of translational medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1940, - "name": "EID1940", - "description": "In a study of 468 colorectal cancer samples, 61 patients had micro-satellite instability and there was a statistically significantly better prognosis for BRAF WT patients relative to BRAF (V600E)-mutated patients (Log-rank P=0.0903).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1367, - "name": "A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC.", - "citation": "Schell et al., 2016, Nat Commun", - "citation_id": "27302369", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27302369", - "open_access": true, - "pmc_id": "PMC4912618", - "publication_date": { - "year": 2016, - "month": 6, - "day": 15 - }, - "journal": "Nat Commun", - "full_journal_title": "Nature communications", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3739, - "name": "EID3739", - "description": "In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with BRAF V600E and wildtype NRAS/KRAS (n=14) mutation treated with FOLFOX4 plus cetuximab were associated with a decreased progression free survival (7.2mo vs. 9.7mo, HR:0.39, 95% CI:0.21-0.72, P=0.0017), and decreased overall survival (11.7mo vs. 28.5mo, HR:0.23, 95% CI:0.12-0.41, P<0.0001), as compared to patients with wildtype BRAF, NRAS and KRAS.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 538, - "name": "FOLFOX-4 Regimen", - "ncit_id": "C63590", - "aliases": [ - "Folinic Acid-Fluororuracil-Oxaliplatin-4 Regimen" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1920, - "name": "FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study.", - "citation": "Kaczirek et al., 2015, Clin Colorectal Cancer", - "citation_id": "25666295", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25666295", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 6 - }, - "journal": "Clin Colorectal Cancer", - "full_journal_title": "Clinical colorectal cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7454, - "name": "EID7454", - "description": "In NCI-MATCH trial, patients with advanced solid tumors, lymphoma or multiple myeloma harboring BRAF V600E mutation were treated with dabrafenib and trametinib.\nPatients with melanoma, thyroid carcinoma, colorectal cancer or NSCLC were excluded.\nThe response rate was 100% (4/4) in patients cholangiocarcinoma and 83% (5/6) in patients with low-grade papillary serous adenocarcinoma of the ovary or mucinous-papillary serous adenocarcinoma of the peritoneum.", - "disease": { - "id": 20, - "name": "Ovarian Cancer", - "display_name": "Ovarian Cancer", - "doid": "2394", - "url": "http://www.disease-ontology.org/?id=DOID:2394" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 2954, - "name": "Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.", - "citation": "April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002", - "citation_id": "172039", - "source_type": "ASCO", - "asco_abstract_id": 3002, - "source_url": "https://meetinglibrary.asco.org/record/172039/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "month": 6 - }, - "journal": "J Clin Oncol 37, 2019 (suppl; abstr 3002)", - "full_journal_title": "Archiv fur experimentelle Veterinarmedizin", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02465060", - "name": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", - "description": "This phase II MATCH trial studies how well treatment that is directed by genetic testing works in patients with solid tumors or lymphomas that have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02465060" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2504, - "name": "EID2504", - "description": "In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1494, - "name": "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.", - "citation": "Elisei et al., 2008, J. Clin. Endocrinol. Metab.", - "citation_id": "18682506", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18682506", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 10 - }, - "journal": "J. Clin. Endocrinol. Metab.", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8646, - "name": "EID8646", - "description": "In a study of metastatic colorectal cancer patients treated with capecitabine, oxaliplatin, bevacizumab, and cetuximab those with BRAF V600E mutations had reduced progression-free survival (6.6mo vs. 10.4mo, P=0.01) and reduced overall survival (15.2mo vs. 21.5mo, P=0.001) compared to those with wildtype BRAF.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 237, - "name": "Oxaliplatin", - "ncit_id": "C1181", - "aliases": [ - "Trans-l Diaminocyclohexane Oxalatoplatinum", - "Trans-l DACH Oxalatoplatinum", - "SR-96669", - "RP-54780", - "RP 54780", - "Oxalatoplatinum", - "Oxalatoplatin", - "Oxalato (trans-l-1,2-diaminocyclohexane)platinum(II)", - "Oxalato (1R,2R-cyclohexanediamine)platinum(II)", - "JM-83", - "Eloxatine", - "ELOXATIN", - "Diaminocyclohexane Oxalatoplatinum", - "DACPLAT", - "Dacotin", - "Aiheng", - "Ai Heng", - "[SP-4-2-(1R-trans)]-(1,2,cyclohexanediamine-N,N')[ethanedioato(2--)-O,O']platinum", - "[(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum", - "1-OHP" - ] - }, - { - "id": 33, - "name": "Bevacizumab", - "ncit_id": "C2039", - "aliases": [ - "Zirabev", - "Mvasi", - "Bevacizumab-bvzr", - "Bevacizumab-awwb", - "Bevacizumab Biosimilar Zirabev", - "Bevacizumab Biosimilar Mvasi", - "Bevacizumab Biosimilar GB-222", - "SCT501", - "RhuMab-VEGF", - "Recombinant Humanized Anti-VEGF Monoclonal Antibody", - "Immunoglobulin G1 (Human-Mouse Monoclonal RhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal RhuMab-VEGF Light Chain, Dimer", - "HD204", - "BP102 Biosimilar", - "BP102", - "Bevacizumab Biosimilar SCT501", - "Bevacizumab Biosimilar RPH-001", - "Bevacizumab Biosimilar QL 1101", - "Bevacizumab Biosimilar MIL60", - "Bevacizumab Biosimilar LY01008", - "Bevacizumab Biosimilar IBI305", - "Bevacizumab Biosimilar HLX04", - "Bevacizumab Biosimilar HD204", - "Bevacizumab Biosimilar FKB238", - "Bevacizumab Biosimilar CT-P16", - "Bevacizumab Biosimilar CBT 124", - "Bevacizumab Biosimilar BI 695502", - "Bevacizumab Biosimilar BEVZ92", - "Bevacizumab Awwb", - "Avastin", - "Anti-VEGF RhuMAb", - "Anti-VEGF Humanized Monoclonal Antibody", - "Anti-VEGF" - ] - }, - { - "id": 32, - "name": "Capecitabine", - "ncit_id": "C1794", - "aliases": [ - "Xeloda", - "Ro 09-1978/000", - "5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 1481, - "name": "BRAF mutation in metastatic colorectal cancer.", - "citation": "Tol et al., 2009, N. Engl. J. Med.", - "citation_id": "19571295", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19571295", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 7, - "day": 2 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3776, - "name": "EID3776", - "description": "In an in vitro study, WiDr, HT-29 and RKO cell lines expressing BRAF V600E mutation was associated with sensitivity to regorafenib treatment, as compared to Caco-2 and KM12SM cells expressing wild-type BRAF. Resistance was determined by assessing cell proliferation and migration.", - "disease": { - "id": 119, - "name": "Colon Cancer", - "display_name": "Colon Cancer", - "doid": "219", - "url": "http://www.disease-ontology.org/?id=DOID:219" - }, - "drugs": [ - { - "id": 27, - "name": "Regorafenib", - "ncit_id": "C78204", - "aliases": [ - "Stivarga", - "BAY 73-4506", - "4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-N-methylpyridine-2-carboxamide" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1973, - "name": "Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma.", - "citation": "Takigawa et al., 2016, Cancer Sci.", - "citation_id": "26865419", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26865419", - "open_access": true, - "pmc_id": "PMC5001714", - "publication_date": { - "year": 2016, - "month": 5 - }, - "journal": "Cancer Sci.", - "full_journal_title": "Cancer science", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2126, - "name": "EID2126", - "description": "Patients with BRAF mutations who were treated with the specific RAF inhibitor dabrafenib had an improved overall survival (P<0.003) compared to untreated patients with BRAF mutations. Patients harboring BRAF mutations were associated with reduced overall survival (11.1mo vs. 46.1mo for wildtype, P=0.006).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1488, - "name": "Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.", - "citation": "Long et al., 2011, J. Clin. Oncol.", - "citation_id": "21343559", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21343559", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 4, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2122, - "name": "EID2122", - "description": "In a mouse in vivo study, the dual RAF and VEGF inhibitor sorafenib suppressed the growth of both UACC903 and 1205Lu cell line- generating xenograft tumors harboring the BRAF-V600E mutation, which had a concomitant reduction of phosphorylated Erk-positive cells (P<0.05).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1484, - "name": "Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors.", - "citation": "Sharma et al., 2005, Cancer Res.", - "citation_id": "15781657", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15781657", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2005, - "month": 3, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3759, - "name": "EID3759", - "description": "In an in vitro study, a melanoma cell line, A375, expressing the BRAF V600E mutation was associated with resistance to dasatinib treatment, comparable to melanoma MEWO cells expressing wild-type BRAF. Resistance was determined by assessing cell viability.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 20, - "name": "Dasatinib", - "ncit_id": "C38713", - "aliases": [ - "Sprycel", - "Dasatinib Monohydrate", - "Dasatinib Hydrate", - "BMS-354825", - "5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-, Monohydrate" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 74, - "name": "Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates.", - "citation": "Woodman et al., 2009, Mol. Cancer Ther.", - "citation_id": "19671763", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19671763", - "open_access": true, - "pmc_id": "PMC3346953", - "publication_date": { - "year": 2009, - "month": 8 - }, - "journal": "Mol. Cancer Ther.", - "full_journal_title": "Molecular cancer therapeutics", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8040, - "name": "EID8040", - "description": "Both in vitro and in vivo models in Kebebew et al. provide evidence that a combinatorial treatment of PLX4720 (a BRAF inhibitor) and ponatinib (a multi targeting tyrosine kinase inhibitor) shows potential efficacy for treatment of thyroid cancer harboring a BRAF V600E mutation. The authors use in vitro data to show that combinatorial therapy of PLX4720 + ponatinib causes less colony formation, increased apoptosis, and reduced MEK and ERK phosphorylation in thyroid cancer cell lines containing a BRAF V600E mutation when compared to the single agents alone and DMSO control as well as compared to WT BRAF thyroid cancer lines. The authors' in vivo model suggests that a combinatorial therapy reduces tumor burden of BRAF V600E thyroid cancer tumors without a significant loss of body weight. They also show that at 6 weeks of treatment, significantly more mice are surviving on the combinatorial treatment when compared to the single agents alone and the control. Lastly, the authors show that in a BRAF inhibitor resistant cell line model, they also find less colony formation capability, increased apoptosis, and reduced MEK and ERK phosphorylation with the combination therapy. Both the in vitro and in vivo data is convincing. However, the in vivo data would be more convincing if the authors had followed the progression of the mice past 6 weeks of treatment and if they had used a WT BRAF model as an additional control. The authors claim that PLX4720 and ponatinib ought to be considered for a clinical trial and their data seems to suggest a similar conclusion and thus validates this claim.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 55, - "name": "Ponatinib", - "ncit_id": "C95777", - "aliases": [ - "Benzamide, 3-(2-Imidazo(1,2-B)Pyridazin-3-Ylethynyl)-4-Methyl-N-(4-((4-Methyl-1- Piperazinyl)Methyl)-3-(Trifluoromethyl)Phenyl)", - "AP24534", - "AP-24534" - ] - }, - { - "id": 30, - "name": "PLX4720", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 3168, - "name": "A combinatorial strategy for targeting BRAF V600E mutant cancers with BRAF V600E inhibitor (PLX4720) and tyrosine kinase inhibitor (ponatinib).", - "citation": "Kebebew et al., 2020, Clin. Cancer Res.", - "citation_id": "31937621", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31937621", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2020, - "month": 1, - "day": 14 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1430, - "name": "EID1430", - "description": "BRAF mutations were identified in 9% of 108 cases of high-grade colorectal neuroendocrine tumors (80% V600E). Two patients were treated with a combination of BRAF and MEK inhibition and exhibited durable response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor DNA correlated with disease response in one of the patients. BRAF and MEK inhibition was either dabrafenib+trametinib (case 1) or vemurafenib+trametinib (case 2).", - "disease": { - "id": 53, - "name": "Gastrointestinal Neuroendocrine Tumor", - "display_name": "Gastrointestinal Neuroendocrine Tumor", - "doid": "0050626", - "url": "http://www.disease-ontology.org/?id=DOID:0050626" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 969, - "name": "BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.", - "citation": "Klempner et al., 2016, Cancer Discov", - "citation_id": "27048246", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27048246", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 6 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 80, - "name": "EID80", - "description": "Thyroid nodule with BRAF V600E mutation is highly correlated with papillary thyroid cancer.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 94, - "name": "Immunohistochemistry for BRAF(V600E) antibody VE1 performed in core needle biopsy samples identifies mutated papillary thyroid cancers.", - "citation": "Crescenzi et al., 2014, Horm. Metab. Res.", - "citation_id": "24570209", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24570209", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 5 - }, - "journal": "Horm. Metab. Res.", - "full_journal_title": "Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et me\u0301tabolisme", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3754, - "name": "EID3754", - "description": "In a stage I melanoma patient harboring a BRAF V600E mutation, response to vemurafenib monotherapy was reported. Upon identification of the BRAF V600E mutation, the patient enrolled in a clinical trial and was treated with vemurafenib monotherapy, a partial response was reported. However, novel hypermetabolic nodules developed and the patient enrolled in another clinical trial, undergoing combination therapy of vemurafenib and GDC-0973, but disease progression occurred at 5 months. Subsequently, the patient was treated with vemurafenib and ipilimumab, achieving a confirmed complete response.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1954, - "name": "Management of a patient with advanced BRAF-mutant melanoma.", - "citation": "Ashworth et al., 2014, J Natl Compr Canc Netw", - "citation_id": "24616537", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24616537", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 3, - "day": 1 - }, - "journal": "J Natl Compr Canc Netw", - "full_journal_title": "Journal of the National Comprehensive Cancer Network : JNCCN", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3741, - "name": "EID3741", - "description": "In an in vitro study, WiDr, HT-29, LS411N, and SW1417 cell lines expressing BRAF V600E and treated with vemurafenib and erlotinib, or vemurafenib and gefitinib were associated with a reduction in cell viability (P<0.01), as compared to cells treated solely with vemurafenib or vehicle. WiDr and HT-29 cell lines expressing BRAF V600E were associated with a modest reduction in cell viability. Sensitivity was determined by assessing cell viability after 72h of vemurafenib treatement. In an in vivo study, WiDr and HT-29 xenografts expression BRAF V600E and treated with vemurafenib and erlotinib combination therapy were associated with reduced tumor volume (P<0.05) as compared to xenografts treated with vemurafenib alone, erlotinib alone, or vehicle alone.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1947, - "name": "EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.", - "citation": "Corcoran et al., 2012, Cancer Discov", - "citation_id": "22448344", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22448344", - "open_access": true, - "pmc_id": "PMC3308191", - "publication_date": { - "year": 2012, - "month": 3 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2144, - "name": "EID2144", - "description": "In a mouse xenograft model, tumors derived from pilocytic astrocytoma cells that expressed BRAF V600E experienced a complete response to treatment with selumetinib, whereas tumors derived from a wildtype BRAF pilocytic astrocytoma cell line were resistant to selumetinib.", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1498, - "name": "Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.", - "citation": "Kolb et al., 2010, Pediatr Blood Cancer", - "citation_id": "20806365", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20806365", - "open_access": true, - "pmc_id": "PMC3004092", - "publication_date": { - "year": 2010, - "month": 10 - }, - "journal": "Pediatr Blood Cancer", - "full_journal_title": "Pediatric blood & cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5958, - "name": "EID5958", - "description": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively.\nWithin the BRAF mutant group, fourteen patients had refractory BRAF V600E-mutated NSCLC (adenocarcinoma, n = 13; sarcomatoid, n = 1). Six patients (43%; 95% CI, 18% to 71%) had objective responses (one CR, five PR), and two additional patients had SD > 120 days. The median DOR was 5 months (range, 4 to 14 months).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2414, - "name": "Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.", - "citation": "Hainsworth et al., 2018, J. Clin. Oncol.", - "citation_id": "29320312", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29320312", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02091141", - "name": "My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors", - "description": "This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02091141" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 99, - "name": "EID99", - "description": "This preclinical study examined vemurafenib efficacy on various colorectal cancer cell lines and in mouse xenograft experiments. Of the cell lines tested, six harbored BRAF V600E (and WT KRAS) and three harbored BRAF WT (but mutant KRAS). Of the six BRAF V600E expressing cell lines, four were sensitive to vemurafenib (IC50 ranging between 0.025 and 0.35 uM; HT29, Colo205, Colo741, LS411N). Cell lines expressing the BRAF V600E mutation responded better to vemurafenib treatment than cells wildtype for BRAF as measured by reduced cellular proliferation and inhibition of MET and ERK phosphorylation (none of the three BRAF wt cell lines had IC50s less than 10uM). Authors note that one of the vemurafenib-resistant cell lines harboring BRAF V600E (RKO) harbored a concurrent activating PIK3CA H1047R mutation. Nude, athymic mice with HT29 xenografts treated with vemurafenib experienced substantial tumor inhibition and increased lifespan at every dose tested, though authors found 75 mg/kg twice daily to be optimal (95% tumor growth inhibition, 90% increased lifespan compared to vehicle treated controls).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 108, - "name": "Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.", - "citation": "Yang et al., 2012, Cancer Res.", - "citation_id": "22180495", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22180495", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 2, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1005, - "name": "EID1005", - "description": "49 BRAF-mutant melanoma cell lines from patients not previously treated with BRAF inhibition were analyzed. 21 exhibited primary resistance to BRAF inhibition using PLX4720. Inhibition of MEK1/2 (AZD6244 [selumetinib]) and PI3K/mTOR (BEZ235 [dactolisib]) was the most effective approach to counteract resistance in comparison to inhibition with the PLX4720 (progenitor of vemurafenib)-BEZ235 (where response was assessed by apoptosis, viability, p-ERK, p-Akt inhibition).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 343, - "name": "Dactolisib", - "ncit_id": "C74072", - "aliases": [ - "NVPBEZ235", - "BEZ235", - "Benzeneacetonitrile, 4-(2,3-Dihydro-3-methyl-2-oxo-8-(3-quinolinyl)-1H-imidazo(4,5-c)quinolin-1-yl)-alpha,alpha-dimethyl-" - ] - }, - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 694, - "name": "Primary cross-resistance to BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma cells counteracted by dual pathway blockade.", - "citation": "Penna et al., 2016, Oncotarget", - "citation_id": "26678033", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26678033", - "open_access": true, - "pmc_id": "PMC4826182", - "publication_date": { - "year": 2016, - "month": 1, - "day": 26 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3773, - "name": "EID3773", - "description": "In a retrospective study of 17 papillary thyroid cancer patients, patients with BRAF V600E mutation (n=6) were associated with a 47% (7/15) partial response rate and a 53% (8/15) stable disease rate.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1970, - "name": "Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience.", - "citation": "Dadu et al., 2015, J. Clin. Endocrinol. Metab.", - "citation_id": "25353071", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25353071", - "open_access": true, - "pmc_id": "PMC4283003", - "publication_date": { - "year": 2015, - "month": 1 - }, - "journal": "J. Clin. Endocrinol. Metab.", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3746, - "name": "EID3746", - "description": "Acquired resistance to vemurafenib in BRAF V600E-positive melanomas frequently confound vemurafenib therapy. Proposed resistance mechanisms include PDGFRB upregulation or NRAS mutations resulting in MAPK pathway reactivation but not secondary mutations in BRAF. MEK inhibitors may demonstrate clinical benefit in vemurafenib resistant melanoma patients.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1491, - "name": "Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.", - "citation": "Nazarian et al., 2010, Nature", - "citation_id": "21107323", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21107323", - "open_access": true, - "pmc_id": "PMC3143360", - "publication_date": { - "year": 2010, - "month": 12, - "day": 16 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1591, - "name": "EID1591", - "description": "Open-label non-randomised phase 2 trial in patients with recurrent or metastatic BRAF V600E mutant papillary thyroid cancer refractory to radioactive iodine. Patients had (cohort 2) or had not (cohort 1) previously been treated with VEGFR inhibitors.\n51 patients were enrolled (26 cohort 1, 25 cohort 2). In cohort 1, partial response was achieved in ten (38.5%) patients. Nine patients achieved stable disease for at least 6 months (35%). Median PFS was 18.2 months and median OS not reached after a median follow-up pf 18.8 months.\nIn cohort 2, six patients (27.3%) achieved a partial response and another six patients achieved stable disease for at least six months. Median PFS was 8.9 months and median OS was 14.4. months.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1052, - "name": "Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.", - "citation": "Brose et al., 2016, Lancet Oncol.", - "citation_id": "27460442", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27460442", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 7, - "day": 22 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01286753", - "name": "A Study of Vemurafenib (RO5185426) in Participants With Metastatic or Unresectable Papillary Thyroid Cancer Positive for the BRAF V600 Mutation", - "description": "This open-label, multi-center study will evaluate the safety and efficacy of Vemurafenib (RO5185426) in participants with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine therapy. Participants will receive vemurafenib 960 milligrams (mg) orally twice daily until progressive disease or unacceptable toxicity occurs.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01286753" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 95, - "name": "EID95", - "description": "Dabrafenib with trametinib provides higher response rate and lower toxicity (as compared to chemotherapy) in patients with melanoma.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 105, - "name": "Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma.", - "citation": "Menzies et al., 2014, Clin. Cancer Res.", - "citation_id": "24583796", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24583796", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 4, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3742, - "name": "EID3742", - "description": "In a clinical study of 122 cancer patients, including 37 previously treated colorectal cancer patients harboring BRAF V600 (V600E=32; V600 unknown=5) mutations, stable disease and progressive disease were reported in 50% of patients (n=5/10) treated with vemurafenib monotherapy, respectively.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7485, - "name": "EID7485", - "description": "In a phase 2 trial, patients with pediatric low-grade glioma after at least one standard therapy were treated with MEK1/2 inhibitor selumetinib.\nIn stratum 1, nine patients with WHO grade I pilocytic astrocytoma harboring KIAA1549-BRAF fusion or BRAF V600E mutation showed tumor response. The response rate was 36% (9/25), with 2/7 (29%) patients with the BRAF V600E variant showing partial response. Also, PFS was shorter in patients with BRAF V600E than those harboring KIAA1549-BRAF fusions.\nIn stratum 3, ten patients with neurofibromatosis type 1 associated pediatric low-grade glioma showed tumor response. The response rate was 40% (10/25).", - "disease": { - "id": 1673, - "name": "Childhood Pilocytic Astrocytoma", - "display_name": "Childhood Pilocytic Astrocytoma", - "doid": "6812", - "url": "http://www.disease-ontology.org/?id=DOID:6812" - }, - "drugs": [ - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 2973, - "name": "Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.", - "citation": "Fangusaro et al., 2019, Lancet Oncol.", - "citation_id": "31151904", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31151904", - "open_access": true, - "pmc_id": "PMC6628202", - "publication_date": { - "year": 2019, - "month": 7 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01089101", - "name": "Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma", - "description": "This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01089101" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3763, - "name": "EID3763", - "description": "A study of pediatric malignant astrocytomas found that tumors with BRAF V600E mutations also had homozygous deletions of CDKN2A more frequently than those with wildtype BRAF (71% vs. 8% , P=0.0016, Fisher\ufffds exact test).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1961, - "name": "Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas.", - "citation": "Schiffman et al., 2010, Cancer Res.", - "citation_id": "20068183", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20068183", - "open_access": true, - "pmc_id": "PMC2851233", - "publication_date": { - "year": 2010, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2146, - "name": "EID2146", - "description": "In a phase 2 clinical trial with 250 metastatic melanoma BRAF-V600E patients, treatment groups were randomly assigned to either dabrafenib, BRAF specific inhibitor, (n=187) or dacarbazine, a standard chemotherapeutic agent (n=63). Patients treated with dabrafenib were associated with improved progression-free survival (5.1mo vs. 2.7mo, HR:0.30, 95% CI:0.18-0.51, P<0.0001) compared with patients undergoing dacarbazine therapy.", - "disease": { - "id": 206, - "name": "Skin Melanoma", - "display_name": "Skin Melanoma", - "doid": "8923", - "url": "http://www.disease-ontology.org/?id=DOID:8923" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1500, - "name": "Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.", - "citation": "Hauschild et al., 2012, Lancet", - "citation_id": "22735384", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22735384", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 7, - "day": 28 - }, - "journal": "Lancet", - "full_journal_title": "Lancet (London, England)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01227889", - "name": "A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma", - "description": "BRF113683 is a Phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of GSK2118436 to dacarbazine (DTIC), in subjects with BRAF mutant advanced (Stage III) or metastatic (Stage IV) melanoma. Subjects will be randomized to receive 150 mg of GSK2118436 twice daily or 1000 mg/m2 DTIC every 3 weeks and continue on treatment until disease progression, death, or unacceptable adverse event. Subjects who progress on DTIC will be allowed to crossover to an optional extension arm of the study to receive GSK2118436.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01227889" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3745, - "name": "EID3745", - "description": "Acquired resistance to vemurafenib in BRAF V600E-positive melanomas frequently confound vemurafenib therapy. Proposed resistance mechanisms include PDGFRB upregulation or NRAS mutations resulting in MAPK pathway reactivation but not secondary mutations in BRAF. MEK inhibitors may demonstrate clinical benefit in vemurafenib resistant melanoma patients.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1492, - "name": "COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.", - "citation": "Johannessen et al., 2010, Nature", - "citation_id": "21107320", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21107320", - "open_access": true, - "pmc_id": "PMC3058384", - "publication_date": { - "year": 2010, - "month": 12, - "day": 16 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5906, - "name": "EID5906", - "description": "Patients with metastatic cholangiocarcinoma havoring with BRAF V600E was treated with vemurafenib, panitumumab and irinotecan triplet therapy. Multiple lung metastasis was dramatically regressed and this treatment was continued.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - }, - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2382, - "name": "Complete Clinical Response of BRAF-Mutated Cholangiocarcinoma to Vemurafenib, Panitumumab, and Irinotecan.", - "citation": "Silkin et al., 2016, J Gastrointest Cancer", - "citation_id": "26687137", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26687137", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 12 - }, - "journal": "J Gastrointest Cancer", - "full_journal_title": "Journal of gastrointestinal cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6938, - "name": "EID6938", - "description": "In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response. The hazard ratio for progression or death in the V600E group was 0.81 for dabrafenib-trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-trametinib group, 68% of patients had a response, which was 15 percentage points higher than in the dabrafenib-alone group (95% CI, 4 to 24; P=0.006).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2671, - "name": "Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.", - "citation": "Long et al., 2014, N. Engl. J. Med.", - "citation_id": "25265492", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25265492", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 11, - "day": 13 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01584648", - "name": "A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma", - "description": "This is a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to dabrafenib administered with a trametinib placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 340 subjects will be randomized 1:1 (combination therapy: dabrafenib monotherapy). Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). The primary endpoint is investigator-assessed, progression-free survival for subjects receiving the combination therapy compared with those receiving dabrafenib monotherapy. Subjects will be followed for overall survival; crossover will not be permitted.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01584648" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 97, - "name": "EID97", - "description": "Combined nutlin-3 and PLX4720 administration to athymic nude mice subcutanousely injected with the A357 colorectal cell line with a BRAF V600E mutation effectively inhibited tumor growth significantly more than single agent therapy.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 31, - "name": "Nutlin-3", - "ncit_id": null, - "aliases": [] - }, - { - "id": 30, - "name": "PLX4720", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 107, - "name": "Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth.", - "citation": "Ji et al., 2013, Clin. Cancer Res.", - "citation_id": "23812671", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23812671", - "open_access": true, - "pmc_id": "PMC3777641", - "publication_date": { - "year": 2013, - "month": 8, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3756, - "name": "EID3756", - "description": "In an in vitro study of 27 melanoma cell lines, 18 out of 20 cell lines expressing BRAF V600E mutation were associated with sensitivity to vemurafenib treatment (IC50: 0.01-1\ufffdM). Sensitivity was determined by assessing growth inhibition.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1956, - "name": "Identification of MET and SRC activation in melanoma cell lines showing primary resistance to PLX4032.", - "citation": "Vergani et al., 2011, Neoplasia", - "citation_id": "22241959", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22241959", - "open_access": true, - "pmc_id": "PMC3257188", - "publication_date": { - "year": 2011, - "month": 12 - }, - "journal": "Neoplasia", - "full_journal_title": "Neoplasia (New York, N.Y.)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2127, - "name": "EID2127", - "description": "Acquired resistance to vemurafenib in BRAF-V600E positive melanomas frequently confound vemurafenib therapy.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 352, - "name": "Inhibition of mutated, activated BRAF in metastatic melanoma.", - "citation": "Flaherty et al., 2010, N. Engl. J. Med.", - "citation_id": "20818844", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20818844", - "open_access": true, - "pmc_id": "PMC3724529", - "publication_date": { - "year": 2010, - "month": 8, - "day": 26 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 126, - "name": "EID126", - "description": "This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 30 patients harbored BRAF V600E, were KRAS, NRAS and PIK3CA wt, and had individual response data. One patient (who harbored BRAF V600E in low copy number) responded, 11 had stable disease, and 18 progressed. Treatments included cetuximab + irinotecan (n=20), cetuximab monotherapy (n=5), cetuximab + FOLFIRI (n=4), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 8 weeks (2-32 weeks), median OS was 25 weeks (4-237 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 61 years old (42-78) and there were 16 males and 14 females. Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 76, - "name": "Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.", - "citation": "De Roock et al., 2010, Lancet Oncol.", - "citation_id": "20619739", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20619739", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 8 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3788, - "name": "EID3788", - "description": "In a malignant peripheral nerve sheath tumor patient harboring a BRAF V600E mutation, response to vemurafenib monotherapy was reported. Upon identification of the BRAF V600E mutation, the patient was treated with sorafenib monotherapy, but quickly progressed; subsequently, the patient was treated with vemurafenib. 33 days after treatment was initiated, tumor response was reported, as evident by the disappearance of chest and abdominal skin lesions.", - "disease": { - "id": 326, - "name": "Malignant Peripheral Nerve Sheath Tumor", - "display_name": "Malignant Peripheral Nerve Sheath Tumor", - "doid": "5940", - "url": "http://www.disease-ontology.org/?id=DOID:5940" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1958, - "name": "Vemurafenib treatment of BRAF V600E-mutated malignant peripheral nerve sheath tumor.", - "citation": "Kaplan, 2013, J Natl Compr Canc Netw", - "citation_id": "24335681", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24335681", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 12, - "day": 1 - }, - "journal": "J Natl Compr Canc Netw", - "full_journal_title": "Journal of the National Comprehensive Cancer Network : JNCCN", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6124, - "name": "EID6124", - "description": "In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively.", - "disease": { - "id": 57, - "name": "Colorectal Adenocarcinoma", - "display_name": "Colorectal Adenocarcinoma", - "doid": "0050861", - "url": "http://www.disease-ontology.org/?id=DOID:0050861" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2468, - "name": "Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.", - "citation": "Corcoran et al., 2018, Cancer Discov", - "citation_id": "29431699", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29431699", - "open_access": true, - "pmc_id": "PMC5882509", - "publication_date": { - "year": 2018 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8033, - "name": "EID8033", - "description": "Ghosh et al. provide compelling evidence that thyroid cancers with a BRAFV600E mutation are sensitive to combined PLX4720 and Ponatinib treatment. They predicted a synergistic effect using HTS of active drugs and validated this prediction both in vitro and in vivo. The treatment combination significantly inhibited the growth of BRAFV600E mutant cancer cell lines, as well as reduced tumor growth, decreased metastases, and increased survival in a thyroid cancer mouse model. The authors recommend that this combination be tested in clinical trials.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 55, - "name": "Ponatinib", - "ncit_id": "C95777", - "aliases": [ - "Benzamide, 3-(2-Imidazo(1,2-B)Pyridazin-3-Ylethynyl)-4-Methyl-N-(4-((4-Methyl-1- Piperazinyl)Methyl)-3-(Trifluoromethyl)Phenyl)", - "AP24534", - "AP-24534" - ] - }, - { - "id": 30, - "name": "PLX4720", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 3168, - "name": "A combinatorial strategy for targeting BRAF V600E mutant cancers with BRAF V600E inhibitor (PLX4720) and tyrosine kinase inhibitor (ponatinib).", - "citation": "Kebebew et al., 2020, Clin. Cancer Res.", - "citation_id": "31937621", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31937621", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2020, - "month": 1, - "day": 14 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3755, - "name": "EID3755", - "description": "In a clinical study (NCT01307397) of Polish, stage IIIC/IV, melanoma patients with metastases (n=75) harboring BRAF V600 mutation (as detected by cobas 4800 BRAF V600 Mutation Test), median overall survival was 61.9% (95% CI: 50.1-73.6) and median progression free survival was 7.4 months (95% CI: 5.5-9.2). Median duration of response was 7.4 months (95% CI: 5.7-9.2), with 3% (2/75) and 43% (29/75) of patients achieving a complete and partial response, respectively.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1955, - "name": "The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial.", - "citation": "Rutkowski et al., 2015, Contemp Oncol (Pozn)", - "citation_id": "26557775", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26557775", - "open_access": true, - "pmc_id": "PMC4631301", - "publication_date": { - "year": 2015 - }, - "journal": "Contemp Oncol (Pozn)", - "full_journal_title": "Contemporary oncology (Poznan, Poland)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1413, - "name": "EID1413", - "description": "Treatment response to mutant BRAF inhibitor vemurafenib and EGFR inhibitor panitumumab was assayed in 12 patients with metastatic colorectal cancer (CRC) who had progressed on chemotherapy. Two patients had confirmed partial responses, and 2 showed stable disease over 6 months. The authors conclude that although some efficacy is seen, only a small subset of patients respond to this treatment and the responses are not durable.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 957, - "name": "Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.", - "citation": "Yaeger et al., 2015, Clin. Cancer Res.", - "citation_id": "25589621", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25589621", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 3, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1406, - "name": "EID1406", - "description": "In trial NCT00880321, dabrafenib was tested in various solid tumor types harboring mutant BRAF after establishing dosage of 150 mg twice daily. In nine colorectal cancer patients with established V600E mutation, 1 confirmed response, 7 instances of stable disease, and 1 case of progressive disease was seen, which contrasted strongly with a 56% confirmed response rate seen in metastatic V600E melanoma patients similarly treated in the same study.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 345, - "name": "Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.", - "citation": "Falchook et al., 2012, Lancet", - "citation_id": "22608338", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22608338", - "open_access": true, - "pmc_id": "PMC4109288", - "publication_date": { - "year": 2012, - "month": 5, - "day": 19 - }, - "journal": "Lancet", - "full_journal_title": "Lancet (London, England)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00880321", - "name": "A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors", - "description": "BRF112680 is a first-time-in-human study to establish the recommended dose and schedule of the orally administered GSK2118436. The recommended dose and regimen will be selected based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after the treatment of subjects with solid tumors. This is a two-part study. Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. The recommended Part 2 dose will be expanded to up to 12 patients. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors. In addition, the effect of GSK2118436 on midazolam will be assessed in a subset of patients in Part 2. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00880321" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5902, - "name": "EID5902", - "description": "Chemotherapy-refractory, metastatic cholangiocarcinoma with BRAF V600E showed dramatically response for Dabrafenib and Trametinib combination.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 548, - "name": "Trametinib Dimethyl Sulfoxide", - "ncit_id": "C152711", - "aliases": [ - "Mekinist" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2381, - "name": "Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion.", - "citation": "Kocsis et al., 2017, J Gastrointest Oncol", - "citation_id": "28480077", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28480077", - "open_access": true, - "pmc_id": "PMC5401859", - "publication_date": { - "year": 2017, - "month": 4 - }, - "journal": "J Gastrointest Oncol", - "full_journal_title": "Journal of gastrointestinal oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3787, - "name": "EID3787", - "description": "A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient, harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was treated with standard chemotherapy, hormone therapy and bevacizumab prior to the identification of the BRAF V600E mutation; next, the patient was treated with paclitaxel and an anti-HER3 antibody and finally with vemurafenib, obtaining a partial response of greater than 1 year.", - "disease": { - "id": 87, - "name": "Ovarian Serous Carcinoma", - "display_name": "Ovarian Serous Carcinoma", - "doid": "0050933", - "url": "http://www.disease-ontology.org/?id=DOID:0050933" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1984, - "name": "Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation.", - "citation": "Combe et al., 2015, Invest New Drugs", - "citation_id": "26490654", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26490654", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 12 - }, - "journal": "Invest New Drugs", - "full_journal_title": "Investigational new drugs", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3790, - "name": "EID3790", - "description": "In a conjunctival malignant melanoma patient harboring a BRAF V600E mutation, BRAF V600E was associated with response to vemurafenib treatment. Prior to identification of the BRAF V600E mutation, the patient was treated with cryotherapy, standard chemotherapy and whole brain radiotherapy; the patient achieved a 4 month progression free survival with vemurafenib treatment prior to disease progression.", - "disease": { - "id": 2605, - "name": "Malignant Conjunctival Melanoma", - "display_name": "Malignant Conjunctival Melanoma", - "doid": "1751", - "url": "http://www.disease-ontology.org/?id=DOID:1751" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1986, - "name": "A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib.", - "citation": "Maleka et al., 2016, BMC Cancer", - "citation_id": "27520988", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27520988", - "open_access": true, - "pmc_id": "PMC4983009", - "publication_date": { - "year": 2016, - "month": 8, - "day": 12 - }, - "journal": "BMC Cancer", - "full_journal_title": "BMC cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3753, - "name": "EID3753", - "description": "In an in vitro study, several cell lines (including MALME-3M, Colo829, Colo38, A375 and SK-MEK28) expressing BRAF V600E were associated with increased sensitivity to vemurafenib (RG7204) treatment, as compared to cell lines expressing BRAF wild-type. Sensitivity was determined by proliferation assay and by assessing MEK1/2 phosphorylation. Further, in an in vivo study, LOX, Colo829 and A375 xenografts were reportedly sensitive to vemurafenib treatment as assessed by tumor volume.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 351, - "name": "RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models.", - "citation": "Yang et al., 2010, Cancer Res.", - "citation_id": "20551065", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20551065", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 7, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3767, - "name": "EID3767", - "description": "In a case report, a hairy cell leukemia (HCL) patient harboring BRAF V600E mutation was associated with a complete response to vemurafenib monotherapy after 3 months of treatment, which was sustained after 21 days of therapy. Prior to vemurafenib treatment, the patient had been diagnosed with HCL and achieved a complete hematologic response to splenectomy and interferon treatment, however, the patient subsequently relapsed and was treated with standard chemotherapy with further disease progression. As a follow-up to a previous study (23300174), a hairy cell leukemia patient harboring BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was previously treated with vemurafenib and obtained a complete response, but then experienced disease progression. Subsequently, the patient was re-treated with vemurafenib and again achieved a complete hematological response.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1964, - "name": "Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation.", - "citation": "Peyrade et al., 2013, Haematologica", - "citation_id": "23300174", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23300174", - "open_access": true, - "pmc_id": "PMC3561446", - "publication_date": { - "year": 2013, - "month": 2 - }, - "journal": "Haematologica", - "full_journal_title": "Haematologica", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3785, - "name": "EID3785", - "description": "In an in vitro study, the BCPAP cell line expressing a BRAF V600E mutation was associated with sensitivity to vemurafenib treatment. Sensitivity was determined by assessing cell viability and apoptotic cell death. However, the 8505C cell line expressing a BRAF V600E mutation and high MET protein phosphorylation levels was reported to be insensitive to vemurafenib treatment.", - "disease": { - "id": 155, - "name": "Thyroid Gland Carcinoma", - "display_name": "Thyroid Gland Carcinoma", - "doid": "3963", - "url": "http://www.disease-ontology.org/?id=DOID:3963" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1982, - "name": "c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.", - "citation": "Byeon et al., 2016, Mol. Carcinog.", - "citation_id": "26456083", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26456083", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 11 - }, - "journal": "Mol. Carcinog.", - "full_journal_title": "Molecular carcinogenesis", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2117, - "name": "EID2117", - "description": "Of 100 metastatic colorectal cancer patients treated with oxaliplatin-based first-line therapy, the 6 patients with either BRAF V600E or D594K had reduced progression-free survival compared to 94 patients with wildtype BRAF (5.0mo vs. 11.7mo, HR:6.4, 95%CI:2.6-15.6, P<0.0001).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 237, - "name": "Oxaliplatin", - "ncit_id": "C1181", - "aliases": [ - "Trans-l Diaminocyclohexane Oxalatoplatinum", - "Trans-l DACH Oxalatoplatinum", - "SR-96669", - "RP-54780", - "RP 54780", - "Oxalatoplatinum", - "Oxalatoplatin", - "Oxalato (trans-l-1,2-diaminocyclohexane)platinum(II)", - "Oxalato (1R,2R-cyclohexanediamine)platinum(II)", - "JM-83", - "Eloxatine", - "ELOXATIN", - "Diaminocyclohexane Oxalatoplatinum", - "DACPLAT", - "Dacotin", - "Aiheng", - "Ai Heng", - "[SP-4-2-(1R-trans)]-(1,2,cyclohexanediamine-N,N')[ethanedioato(2--)-O,O']platinum", - "[(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum", - "1-OHP" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1479, - "name": "Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.", - "citation": "Souglakos et al., 2009, Br. J. Cancer", - "citation_id": "19603024", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19603024", - "open_access": true, - "pmc_id": "PMC2720232", - "publication_date": { - "year": 2009, - "month": 8, - "day": 4 - }, - "journal": "Br. J. Cancer", - "full_journal_title": "British journal of cancer", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 79, - "name": "EID79", - "description": "BRAF V600E is shown to be associated with the tall-cell variant of papillary thyroid cancer.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 93, - "name": "Both BRAF V600E mutation and older age (\u2265 65 years) are associated with recurrent papillary thyroid cancer.", - "citation": "Howell et al., 2011, Ann. Surg. Oncol.", - "citation_id": "21594703", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21594703", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 12 - }, - "journal": "Ann. Surg. Oncol.", - "full_journal_title": "Annals of surgical oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 90, - "name": "EID90", - "description": "In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP and resistance to RAF inhibitors.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 98, - "name": "Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.", - "citation": "Nissan et al., 2014, Cancer Res.", - "citation_id": "24576830", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24576830", - "open_access": true, - "pmc_id": "PMC4005042", - "publication_date": { - "year": 2014, - "month": 4, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6178, - "name": "EID6178", - "description": "Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 792 (91%) patients had V600E, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 150/397 patients (38%) in the treatment group and 229/395 patients (58%) in the placebo group for a 95% CI Hazard Ratio of 0.48 (0.39-0.58).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2475, - "name": "Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.", - "citation": "Long et al., 2017, N. Engl. J. Med.", - "citation_id": "28891408", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28891408", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017, - "day": 9 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01682083", - "name": "A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection.", - "description": "This is a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma will be screened for eligibility. Subjects will be randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or two placebos for 12 months.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01682083" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3757, - "name": "EID3757", - "description": "In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167) complete response, a 58.1% (97/167) partial response and stable disease in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring BRAF V600E experienced progressive disease.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1957, - "name": "A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.", - "citation": "Ugurel et al., 2015, Ann. Oncol.", - "citation_id": "25524477", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25524477", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 3 - }, - "journal": "Ann. Oncol.", - "full_journal_title": "Annals of oncology : official journal of the European Society for Medical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3789, - "name": "EID3789", - "description": "A primary central nervous system (CNS)-histiocytic sarcoma patient harboring BRAF V600E mutation was associated with improved response to vemurafenib treatment. The patient was treated with vemurafenib monotherapy and obtained a clinical, biological and radiologic response; subsequently, the patient developed progressive disease and died 6 months after initial treatment with vemurafenib.", - "disease": { - "id": 964, - "name": "Histiocytoma", - "display_name": "Histiocytoma", - "doid": "4231", - "url": "http://www.disease-ontology.org/?id=DOID:4231" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1985, - "name": "Dramatic response of a BRAF V600E-mutated primary CNS histiocytic sarcoma to vemurafenib.", - "citation": "Idbaih et al., 2014, Neurology", - "citation_id": "25209580", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25209580", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 10, - "day": 14 - }, - "journal": "Neurology", - "full_journal_title": "Neurology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2139, - "name": "EID2139", - "description": "Thyroid cancer cell lines with BRAF V600E mutations were more sensitive to the MEK inhibitor RDEA119 than those with wildtype BRAF (IC50: 0.034-0.217 uM vs. 1.413-34.120 uM).", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 463, - "name": "RDEA 119", - "ncit_id": null, - "aliases": [] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1496, - "name": "BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus.", - "citation": "Liu et al., 2010, Int. J. Cancer", - "citation_id": "21351275", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21351275", - "open_access": true, - "pmc_id": "PMC2916062", - "publication_date": { - "year": 2010, - "month": 12, - "day": 15 - }, - "journal": "Int. J. Cancer", - "full_journal_title": "International journal of cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 463, - "name": "EID463", - "description": "In patients with multiple myeloma, those with BRAF V600E had shorter overall survival than wild-type.", - "disease": { - "id": 41, - "name": "Multiple Myeloma", - "display_name": "Multiple Myeloma", - "doid": "9538", - "url": "http://www.disease-ontology.org/?id=DOID:9538" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 278, - "name": "Targeting the BRAF V600E mutation in multiple myeloma.", - "citation": "Andrulis et al., 2013, Cancer Discov", - "citation_id": "23612012", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23612012", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 8 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7761, - "name": "EID7761", - "description": "In a phase 2 trial, patients with radioiodine refractory papillary thyroid carcinoma harboring BRAF mutation were treated with dabrafenib alone or combination with trametinib. 94% patients havd BRAF V600E.\nResponse rate was 50% (11/22) for dabrafenib and 54% (13/24) for dabrafenb and trametinib combination.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3096, - "name": "Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.", - "citation": "Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022", - "citation_id": "145877", - "source_type": "ASCO", - "asco_abstract_id": 6022, - "source_url": "https://meetinglibrary.asco.org/record/145877/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017, - "month": 1, - "day": 12 - }, - "journal": "J Clin Oncol 35, 2017 (suppl; abstr 6022)", - "full_journal_title": "Biochimica et biophysica acta", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01723202", - "name": "Dabrafenib With or Without Trametinib in Treating Patients With Recurrent Thyroid Cancer", - "description": "This randomized phase II trial studies how well dabrafenib works with or without trametinib in treating patients with recurrent thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether dabrafenib is more effective when given with or without trametinib in treating thyroid cancer", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01723202" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6045, - "name": "EID6045", - "description": "In a phase 2 \u201cbasket\u201d study of vemurafenib in BRAF V600-positive non-melanoma cancers, seven patients with anaplastic thyroid cancer were enrolled. All 7 patients had V600E mutations. One complete response and one partial response was observed, for a response rate of 29%.", - "disease": { - "id": 3040, - "name": "Thyroid Gland Anaplastic Carcinoma", - "display_name": "Thyroid Gland Anaplastic Carcinoma", - "doid": "0080522", - "url": "http://www.disease-ontology.org/?id=DOID:0080522" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2128, - "name": "EID2128", - "description": "An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1579, - "name": "EID1579", - "description": "Two clinical trials evaluated the effects of vemurafenib in 54 patients with BRAF (V600E) positive hairy-cell leukemia. The overall response rate was 98% with 19/54 having a complete response and 34/54 having a partial response. In the Italian study (n=25), the median relapse-free survival was 9 months and in the U.S. study (n=24), rate of progression-free survival was 73% with overall survival rate of 91%.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1043, - "name": "Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.", - "citation": "Tiacci et al., 2015, N. Engl. J. Med.", - "citation_id": "26352686", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26352686", - "open_access": true, - "pmc_id": "PMC4811324", - "publication_date": { - "year": 2015, - "month": 10, - "day": 29 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01711632", - "name": "BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia", - "description": "The purpose of this study is to find out what effects, good and/or bad, treatment with vemurafenib (also known as Zelboraf\u2122) has on the patient and on leukemia. Specifically, the researchers want to know how well vemurafenib eliminates leukemia from the blood.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01711632" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2129, - "name": "EID2129", - "description": "In a mouse in vivo study, the MEK protein inhibitor selumetinib suppressed the growth of 1205Lu xenograft tumors, which contains the BRAF-V600Emutation (0.91 +/- 0.10-fold volume increase vs. 9.47 +/- 2.14-fold for non-treated mice). These tumors had a concomitant reduction of BrdU positive cells (P=0.009) but no increase in apoptosis. Selumetinib, in combination with docetaxel, a chemotherapeutic agent, produced cycle arrest and elevated apoptosis.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 63, - "name": "Selumetinib", - "ncit_id": "C66939", - "aliases": [ - "MEK Inhibitor AZD6244", - "AZD6244", - "ARRY-142886" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1489, - "name": "The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel.", - "citation": "Haass et al., 2008, Clin. Cancer Res.", - "citation_id": "18172275", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18172275", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 1, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3780, - "name": "EID3780", - "description": "In a lung adenocarcinoma patient with brain metastases harboring BRAF V600E mutation, BRAF V600E was associated with sensitivity to vemurafenib treatment. Upon treatment with vemurafenib monotherapy, the patient\ufffds metastases demonstrated significant response and pleural right effusion improvement was observed; however, at 4 months the patient\ufffds disease progressed resulting in death.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1977, - "name": "BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib.", - "citation": "Robinson et al., 2014, Lung Cancer", - "citation_id": "24888229", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24888229", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 8 - }, - "journal": "Lung Cancer", - "full_journal_title": "Lung cancer (Amsterdam, Netherlands)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 103, - "name": "EID103", - "description": "V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 110, - "name": "BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis.", - "citation": "Chen et al., 2014, PLoS ONE", - "citation_id": "24594804", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24594804", - "open_access": true, - "pmc_id": "PMC3940924", - "publication_date": { - "year": 2014 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3736, - "name": "EID3736", - "description": "In metastatic colorectal cancer patients with wildtype KRAS status who received cetuximab therapy, those with a BRAF V600E mutation had reduced progression-free survival (8.0wk vs. 31.4wk, P=0.001, log-rank test, univariate analysis) and reduced overall survival (6.5mo vs. 14.8mo, P=0.001, log-rank test, univariate analysis; HR:6.6, 95%CI:2.4-18.2, P<0.001, multivariate analysis. Similar associations have been found in independent studies.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1945, - "name": "Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.", - "citation": "Laurent-Puig et al., 2009, J. Clin. Oncol.", - "citation_id": "19884556", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19884556", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 12, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3769, - "name": "EID3769", - "description": "As a follow-up to a previous study (23300174), a hairy cell leukemia patient harboring BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was previously treated with vemurafenib and obtained a complete response, but then experienced disease progression. Subsequently, the patient was re-treated with vemurafenib and again achieved a complete hematological response.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1966, - "name": "Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.", - "citation": "Bailleux et al., 2015, Oncoscience", - "citation_id": "25815361", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25815361", - "open_access": true, - "pmc_id": "PMC4341463", - "publication_date": { - "year": 2015 - }, - "journal": "Oncoscience", - "full_journal_title": "Oncoscience", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1398, - "name": "EID1398", - "description": "The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor vemurafenib versus dacarbazine in 598 patients with treatment naive metastatic melanoma and confirmed V600E mutation. Significant differences were seen in overall survival (13.3 months with vemurafenib vs. 10.0 months with dacarbazine) and median progression free survival (6.9 months with vemurafenib vs. 1.6 months with dacarbazine)", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 947, - "name": "Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.", - "citation": "McArthur et al., 2014, Lancet Oncol.", - "citation_id": "24508103", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24508103", - "open_access": true, - "pmc_id": "PMC4382632", - "publication_date": { - "year": 2014, - "month": 3 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01006980", - "name": "A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3)", - "description": "This randomized, open-label study evaluated the efficacy, safety and tolerability of vemurafenib (RO5185426) as compared to dacarbazine in previously untreated patients with metastatic melanoma. Patients were randomized to receive either vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Study treatment was continued until disease progression or unacceptable toxicity occurred. The data and safety monitoring board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011, as both overall survival and progression-free survival endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01006980" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3744, - "name": "EID3744", - "description": "In an 80 year old female anaplastic thyroid cancer patient harboring BRAF V600E and TP53 E180K co-mutations, BRAF V600E was associated with response to vemurafenib treatment. Prior to identification of the BRAF V600E mutation, the patient was treated with 6 cycles of standard chemotherapy plus radiation and experienced progressive disease; subsequently, the patient achieved an almost complete response with 61 weeks of vemurafenib monotherapy followed by disease progression.", - "disease": { - "id": 3040, - "name": "Thyroid Gland Anaplastic Carcinoma", - "display_name": "Thyroid Gland Anaplastic Carcinoma", - "doid": "0080522", - "url": "http://www.disease-ontology.org/?id=DOID:0080522" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1949, - "name": "Sustained Response to Vemurafenib in a BRAF(V600E)-Mutated Anaplastic Thyroid Carcinoma Patient.", - "citation": "Prager et al., 2016, Thyroid", - "citation_id": "27532222", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27532222", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 10 - }, - "journal": "Thyroid", - "full_journal_title": "Thyroid : official journal of the American Thyroid Association", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3752, - "name": "EID3752", - "description": "In an in vitro study, a MBA72 cell line expressing BRAF V600E demonstrated improved sensitivity to vemurafenib treatment, compared to LND-1 cells expression BRAF wild-type. Sensitivity was determined by assessing cell proliferation (MBA72, IC50: 3.2uM; vs. LND-1, IC50: 32.2 uM).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1953, - "name": "Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel better than vemurafenib?", - "citation": "Porcelli et al., 2015, Cancer Chemother. Pharmacol.", - "citation_id": "26070258", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26070258", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 8 - }, - "journal": "Cancer Chemother. Pharmacol.", - "full_journal_title": "Cancer chemotherapy and pharmacology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3770, - "name": "EID3770", - "description": "A hairy cell leukemia patient with extensive CNS involvement patient harboring BRAF V600E mutation was associated with complete response to vemurafenib monotherapy. Upon identification of the BRAF V600E mutation, the patient was treated with cytarabine, rituximab and methotrexate but quickly progressed; subsequently, the patient was treated with 2 rounds of vemurafenib and achieved complete response.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1967, - "name": "Response of relapsed central nervous system hairy cell leukemia to vemurafenib.", - "citation": "McDowell et al., 2016, Leuk. Lymphoma", - "citation_id": "27116997", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27116997", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 12 - }, - "journal": "Leuk. Lymphoma", - "full_journal_title": "Leukemia & lymphoma", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1409, - "name": "EID1409", - "description": "Phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. A relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression was observed with vemurafenib as compared with dacarbazine (P<0.001 for both comparisons).", - "disease": { - "id": 206, - "name": "Skin Melanoma", - "display_name": "Skin Melanoma", - "doid": "8923", - "url": "http://www.disease-ontology.org/?id=DOID:8923" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 954, - "name": "Improved survival with vemurafenib in melanoma with BRAF V600E mutation.", - "citation": "Chapman et al., 2011, N. Engl. J. Med.", - "citation_id": "21639808", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21639808", - "open_access": true, - "pmc_id": "PMC3549296", - "publication_date": { - "year": 2011, - "month": 6, - "day": 30 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01006980", - "name": "A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3)", - "description": "This randomized, open-label study evaluated the efficacy, safety and tolerability of vemurafenib (RO5185426) as compared to dacarbazine in previously untreated patients with metastatic melanoma. Patients were randomized to receive either vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Study treatment was continued until disease progression or unacceptable toxicity occurred. The data and safety monitoring board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011, as both overall survival and progression-free survival endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01006980" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5959, - "name": "EID5959", - "description": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively.\nAmong 4 patients with BRAF V600E mutant ovarian cancer, 2 had a partial response and one had stable disease > 120days.", - "disease": { - "id": 20, - "name": "Ovarian Cancer", - "display_name": "Ovarian Cancer", - "doid": "2394", - "url": "http://www.disease-ontology.org/?id=DOID:2394" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2414, - "name": "Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.", - "citation": "Hainsworth et al., 2018, J. Clin. Oncol.", - "citation_id": "29320312", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29320312", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02091141", - "name": "My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors", - "description": "This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02091141" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6940, - "name": "EID6940", - "description": "In this Phase I and II study (NCT01072175) patients with metastatic melanoma were given dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy. From V600E patients, 45 received monotherapy and 92 received combination therapy. Hazard ratio for progression or death was 0.43 (95% CI, 0.27-0.71). Both patients with the BRAF V600E and V600K mutation showed significant improvement in progression-free survival.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 103, - "name": "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.", - "citation": "Flaherty et al., 2012, N. Engl. J. Med.", - "citation_id": "23020132", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23020132", - "open_access": true, - "pmc_id": "PMC3549295", - "publication_date": { - "year": 2012, - "month": 11 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01072175", - "name": "Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212", - "description": "This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01072175" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3774, - "name": "EID3774", - "description": "In a clinical trial (NCT01286753) of 55 cancer patients with BRAF V600E mutation, patients with metastatic papillary thyroid cancer (n=3) were associated with sensitivity to vemurafenib treatment. One patient achieved partial response (31% reduction by RECIST) and two patients achieved stable disease (9% and 16% reduction by RECIST criteria), the time to progression for these three patients was 11.7, 13.2 and 11.4 months, and the overall survival was 15 months (patient was subsequently treated with radiation therapy), at least 31.7 months (patient subsequently underwent laryngectomy) and 24.9 months (patient was subsequently treated with sorafenib, followed by sunitinib monotherapy), respectively.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1971, - "name": "Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation.", - "citation": "Kim et al., 2013, Thyroid", - "citation_id": "23489023", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23489023", - "open_access": true, - "pmc_id": "PMC3967415", - "publication_date": { - "year": 2013, - "month": 10 - }, - "journal": "Thyroid", - "full_journal_title": "Thyroid : official journal of the American Thyroid Association", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00215605", - "name": "Study of XL184 (Cabozantinib) in Adults With Advanced Malignancies", - "description": "The purpose of this study is to determine the best and safest dose of XL184 administered orally. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. To determine the highest safe dose, subjects will receive different amounts of the drug. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. When the maximum tolerated dose (MTD) is reached, at least 20 subjects with Medullary Thyroid Cancer (MTC) will be enrolled to evaluate the effect of XL184 in this population.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00215605" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7264, - "name": "EID7264", - "description": "In a phase II trial, patients with BRAF V600E mutations in 9 rare tumor types, including BTC received Dabrafenib and Trametinib.\nThirty-three patients with biliary tract cancer had enrolled. 32 of 33 patients were evaluable for efficacy. Overall response rate was 41% (13/32; 95% CI, 24 - 59%). Median PFS was 7.2 months (95% CI, 4.6 - 10.1 months), and median OS was 11.3 months (95% CI, 7.3 - 17.6 months).", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 2860, - "name": "Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated biliary tract cancer (BTC): A cohort of the ROAR basket trial.", - "citation": "Zev A. Wainberg, 2019, Gastrointestinal Cancers Symposium, Abstract 187", - "citation_id": "169315", - "source_type": "ASCO", - "asco_abstract_id": 187, - "source_url": "https://meetinglibrary.asco.org/record/169315/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "month": 3, - "day": 10 - }, - "journal": "J Clin Oncol 37, 2019 (suppl 4; abstr 187)", - "full_journal_title": "Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02034110", - "name": "Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers", - "description": "This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects will need to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options will be eligible for enrollment. Subjects will undergo screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02034110" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3761, - "name": "EID3761", - "description": "In an in vitro study, the HCC364 cell line expressing a BRAF V600E mutation was associated with sensitivity to vemurafenib treatment. Sensitivity was determined by assessing cell viability, apoptosis and colony formation.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1960, - "name": "Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer.", - "citation": "Joshi et al., 2015, PLoS ONE", - "citation_id": "25706985", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25706985", - "open_access": true, - "pmc_id": "PMC4338247", - "publication_date": { - "year": 2015 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2141, - "name": "EID2141", - "description": "In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis.", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 463, - "name": "RDEA 119", - "ncit_id": null, - "aliases": [] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1494, - "name": "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.", - "citation": "Elisei et al., 2008, J. Clin. Endocrinol. Metab.", - "citation_id": "18682506", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18682506", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 10 - }, - "journal": "J. Clin. Endocrinol. Metab.", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3764, - "name": "EID3764", - "description": "In a study of pilocytic astrocytomas, presence of the BRAF V600E mutation was more frequently detected in extra-cerebellar pilocytic astrocytomas than cerebellar ones (20% vs. 2% , P=0.009, Fisher\ufffds exact test).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1962, - "name": "Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.", - "citation": "Schindler et al., 2011, Acta Neuropathol.", - "citation_id": "21274720", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21274720", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 3 - }, - "journal": "Acta Neuropathol.", - "full_journal_title": "Acta neuropathologica", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 86, - "name": "EID86", - "description": "In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP but does not show resistance to MEK inhibitors.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 29, - "name": "Mirdametinib", - "ncit_id": "C52195", - "aliases": [ - "PD 901", - "MEK Inhibitor PD0325901", - "PD0325901", - "PD-0325901" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 98, - "name": "Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.", - "citation": "Nissan et al., 2014, Cancer Res.", - "citation_id": "24576830", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24576830", - "open_access": true, - "pmc_id": "PMC4005042", - "publication_date": { - "year": 2014, - "month": 4, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2131, - "name": "EID2131", - "description": "An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1410, - "name": "EID1410", - "description": "Phase 2 trial in 132 patients with previously treated metastatic melanoma with BRAF V600E mutation. \nConfirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Median overall survival was 15.9 months (95% CI, 11.6 to 18.3).", - "disease": { - "id": 206, - "name": "Skin Melanoma", - "display_name": "Skin Melanoma", - "doid": "8923", - "url": "http://www.disease-ontology.org/?id=DOID:8923" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 354, - "name": "Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.", - "citation": "Sosman et al., 2012, N. Engl. J. Med.", - "citation_id": "22356324", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22356324", - "open_access": true, - "pmc_id": "PMC3724515", - "publication_date": { - "year": 2012, - "month": 2, - "day": 23 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00949702", - "name": "A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma", - "description": "This open-label single arm study will assess the efficacy, safety and tolerability of Vemurafenib in previously treated patients with metastatic melanoma. Patients will receive oral Vemurafenib [RG7204; PLEXXIKON: PLX4032] at a dose of 960 mg b.i.d. continuously until disease progression or withdrawal from study and will be assessed at regular intervals for tumour response and tolerability. Target sample size is <100 patients.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00949702" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2143, - "name": "EID2143", - "description": "In a genetic screen of 87 lung cancer cell lines, one MEK-dependent cell line HCC364 contained a BRAF-V600E mutation. In growth assays, the MEK inhibitor PD-0325901 reduced proliferation in growth assays of the HCC364 cell line (IC50=3.2 nmol/L). Additionally, cells exposed to PD-0325901 exhibited an increase in apoptosis, as measured by induction of PARP cleavage.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 29, - "name": "Mirdametinib", - "ncit_id": "C52195", - "aliases": [ - "PD 901", - "MEK Inhibitor PD0325901", - "PD0325901", - "PD-0325901" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 341, - "name": "Genetic predictors of MEK dependence in non-small cell lung cancer.", - "citation": "Pratilas et al., 2008, Cancer Res.", - "citation_id": "19010912", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19010912", - "open_access": true, - "pmc_id": "PMC2649746", - "publication_date": { - "year": 2008, - "month": 11, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 105, - "name": "EID105", - "description": "BRAF mutation correlated with poor prognosis in papillary thyroid cancer in both older (>65 yo) and younger (<65 yo) cohorts.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 93, - "name": "Both BRAF V600E mutation and older age (\u2265 65 years) are associated with recurrent papillary thyroid cancer.", - "citation": "Howell et al., 2011, Ann. Surg. Oncol.", - "citation_id": "21594703", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21594703", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 12 - }, - "journal": "Ann. Surg. Oncol.", - "full_journal_title": "Annals of surgical oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3740, - "name": "EID3740", - "description": "In a retrospective study of 53, KRAS exon 2 wild-type, metastatic colorectal cancer patients, patients harboring BRAF G466A (n=1), G469A (n=2), D594G (n=1), or V600E (n=2) mutations were reported to be non-responders to cetuximab in combination with irinotecan, (BRAF mutation positive: responders vs. non-responders = 0 vs. 6; BRAF wild-type: responders vs. non-responders 30 vs. 17; P=0.004), as compared to patients with wild-type BRAF.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1946, - "name": "Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients.", - "citation": "Hsu et al., 2016, Oncotarget", - "citation_id": "26989027", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26989027", - "open_access": true, - "pmc_id": "PMC5008360", - "publication_date": { - "year": 2016, - "month": 4, - "day": 19 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3778, - "name": "EID3778", - "description": "A grade I refractory brainstem ganglioglioma patient harboring BRAF V600E mutation was associated with partial response to vemurafenib monotherapy. The patient experienced significant clinical improvement in response to vemurafenib and maintained a partial response for 12 months; however, disease progression occurred after vemurafenib was discontinued for three months, reintroduction of vemurafenib resulted in a rapid partial response, with continued response noted at time of publication.", - "disease": { - "id": 2604, - "name": "Ganglioglioma", - "display_name": "Ganglioglioma", - "doid": "5078", - "url": "http://www.disease-ontology.org/?id=DOID:5078" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1975, - "name": "Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.", - "citation": "Aguilera et al., 2016, Pediatr Blood Cancer", - "citation_id": "26579623", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26579623", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 3 - }, - "journal": "Pediatr Blood Cancer", - "full_journal_title": "Pediatric blood & cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5903, - "name": "EID5903", - "description": "Two cases of patients with BRAF V600E positive cholangiocarcinoma showed excellent response for Dabrafenib and Trametinib.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 548, - "name": "Trametinib Dimethyl Sulfoxide", - "ncit_id": "C152711", - "aliases": [ - "Mekinist" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2380, - "name": "Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review.", - "citation": "Lavingia et al., 2016, J Gastrointest Oncol", - "citation_id": "28078132", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28078132", - "open_access": true, - "pmc_id": "PMC5177579", - "publication_date": { - "year": 2016, - "month": 12 - }, - "journal": "J Gastrointest Oncol", - "full_journal_title": "Journal of gastrointestinal oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3827, - "name": "EID3827", - "description": "One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic colorectal cancer had a tumor which harbored BRAF V600E, was wildtype for NRAS, KRAS and PIK3CA, and had individual response data. This patient was was a male treated with panitumumab monotherapy as 1st line therapy who experienced progressive disease (PFS: 7 weeks; OS: 10 weeks).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 76, - "name": "Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.", - "citation": "De Roock et al., 2010, Lancet Oncol.", - "citation_id": "20619739", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20619739", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 8 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3772, - "name": "EID3772", - "description": "A pediatric pilocytic astrocytoma patient harboring BRAF V600E mutation, BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was treated with standard chemotherapy regimens prior to the identification of the BRAF V600E mutation; subsequently, vemurafenib was administered (initially in combination with standard chemotherapy) and an overall regression achieved, with lack of disease progression noted at 15 months of vemurafenib therapy.", - "disease": { - "id": 166, - "name": "Pilocytic Astrocytoma", - "display_name": "Pilocytic Astrocytoma", - "doid": "4851", - "url": "http://www.disease-ontology.org/?id=DOID:4851" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1969, - "name": "Pilomyxoid astrocytoma treated successfully with vemurafenib.", - "citation": "Skrypek et al., 2014, Pediatr Blood Cancer", - "citation_id": "24821190", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24821190", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 11 - }, - "journal": "Pediatr Blood Cancer", - "full_journal_title": "Pediatric blood & cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 6975, - "name": "EID6975", - "description": "Interim analysis of a basket trial evaluating the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously treated V600E-mutated patients showed 11/16 patients with anaplastic thyroid carcinoma responded to treatment (overall response rate 69%; 95% CI, 41% to 89%). Seven patients had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached after 120 weeks.", - "disease": { - "id": 3040, - "name": "Thyroid Gland Anaplastic Carcinoma", - "display_name": "Thyroid Gland Anaplastic Carcinoma", - "doid": "0080522", - "url": "http://www.disease-ontology.org/?id=DOID:0080522" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2686, - "name": "Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.", - "citation": "Subbiah et al., 2018, J. Clin. Oncol.", - "citation_id": "29072975", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29072975", - "open_access": true, - "pmc_id": "PMC5791845", - "publication_date": { - "year": 2018, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02034110", - "name": "Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers", - "description": "This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects will need to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options will be eligible for enrollment. Subjects will undergo screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02034110" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3748, - "name": "EID3748", - "description": "An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3766, - "name": "EID3766", - "description": "In a refractory hairy cell leukemia patient harboring BRAF V600E mutation, BRAF V600E was associated with sensitivity to vemurafenib treatment. The patient was initially treated with conventional treatments and failed to respond; subsequently, the patient was treated with vemurafenib monotherapy and achieved complete remission on day 43 with treatment being terminated at day 56.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1963, - "name": "BRAF inhibition in refractory hairy-cell leukemia.", - "citation": "Dietrich et al., 2012, N. Engl. J. Med.", - "citation_id": "22621641", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22621641", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 5, - "day": 24 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3783, - "name": "EID3783", - "description": "A stage IV lung adenocarcinoma patient harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient\ufffds prior treatment regimens were complex, including radiotherapy, standard chemotherapy and erlotinib; subsequently, the BRAF V600E mutation was identified and the patient was treated with vemurafenib monotherapy, achieving a favorable response for greater than 24 months.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1980, - "name": "Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene.", - "citation": "Myall et al., 2016, Clin Lung Cancer", - "citation_id": "26776917", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26776917", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 3 - }, - "journal": "Clin Lung Cancer", - "full_journal_title": "Clinical lung cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3765, - "name": "EID3765", - "description": "In a study of low grade pediatric gliomas, 19 of 157 tumors had a BRAF V600E mutation. Tumors located in the cerebrum had a higher frequency of BRAF mutations than those in the cerebellum or midline (P<0.05). While it did not reach statistical significance, there was a trend between BRAF V600E mutation and reduced progression-free survival (HR:2.39, 95%CI:0.93-6.15, P=0.07, multivariate analysis).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 1499, - "name": "Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.", - "citation": "Horbinski et al., 2012, Neuro-oncology", - "citation_id": "22492957", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22492957", - "open_access": true, - "pmc_id": "PMC3367847", - "publication_date": { - "year": 2012, - "month": 6 - }, - "journal": "Neuro-oncology", - "full_journal_title": "Neuro-oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7260, - "name": "EID7260", - "description": "In a phase III trial, patients with BRAF V600E mutated metastatic colorectal cancer received triplet combination with encorafenib + binimetinib + cetuximab in a second or third-line setting. In the safety-lead in part of this trial, 30 patients were given triplet therapy, of which 29 with V600E mutation were included in the efficacy analysis. The objective response rate was 48% [95%CI: 29.4 - 67.5], median PFS was 8.0 mo [95%CI: 5.6 - 9.3], and median OS was 15.3 mo [95%CI: 9.6 - not reached]. The author concluded that triplet therapy was well tolerated and PFS and OS were substantially improved over historical standard of care.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 485, - "name": "Binimetinib", - "ncit_id": "C84865", - "aliases": [ - "Mektovi", - "MEK162", - "ARRY-438162", - "ARRY-162" - ] - }, - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2858, - "name": "Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).", - "citation": "Scott Kopetz, 2019, Gastrointestinal Cancers Symposium, Abstract 688", - "citation_id": "168986", - "source_type": "ASCO", - "asco_abstract_id": 688, - "source_url": "https://meetinglibrary.asco.org/record/168986/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "month": 9 - }, - "journal": "J Clin Oncol 37, 2019 (suppl 4; abstr 688)", - "full_journal_title": "Circulation research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02928224", - "name": "Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer", - "description": "This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02928224" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 5962, - "name": "EID5962", - "description": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant laryngeal cancer had a partial response with vemurafenib.", - "disease": { - "id": 124, - "name": "Laryngeal Squamous Cell Carcinoma", - "display_name": "Laryngeal Squamous Cell Carcinoma", - "doid": "2876", - "url": "http://www.disease-ontology.org/?id=DOID:2876" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2414, - "name": "Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.", - "citation": "Hainsworth et al., 2018, J. Clin. Oncol.", - "citation_id": "29320312", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29320312", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02091141", - "name": "My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors", - "description": "This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02091141" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1127, - "name": "EID1127", - "description": "In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E mutation in all 47 of the sequenced patients.", - "disease": { - "id": 665, - "name": "Hairy Cell Leukemia", - "display_name": "Hairy Cell Leukemia", - "doid": "285", - "url": "http://www.disease-ontology.org/?id=DOID:285" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 780, - "name": "BRAF mutations in hairy-cell leukemia.", - "citation": "Tiacci et al., 2011, N. Engl. J. Med.", - "citation_id": "21663470", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21663470", - "open_access": true, - "pmc_id": "PMC3689585", - "publication_date": { - "year": 2011, - "month": 6, - "day": 16 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3786, - "name": "EID3786", - "description": "An anaplastic pleomorphic xanthoastrocytoma patient harboring BRAF V600E mutation was associated with improved response to vemurafenib treatment. The patient was treated with radiation and temozolomide before experiencing disease progression; subsequent treatment with vemurafenib monotherapy, for a 12 week period, resulted in a near complete response.", - "disease": { - "id": 1124, - "name": "Pleomorphic Xanthoastrocytoma", - "display_name": "Pleomorphic Xanthoastrocytoma", - "doid": "4852", - "url": "http://www.disease-ontology.org/?id=DOID:4852" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1983, - "name": "Successful Treatment of a Progressive BRAF V600E-Mutated Anaplastic Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy.", - "citation": "Lee et al., 2016, J. Clin. Oncol.", - "citation_id": "25092772", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25092772", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 4, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02034110", - "name": "Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers", - "description": "This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects will need to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options will be eligible for enrollment. Subjects will undergo screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02034110" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2134, - "name": "EID2134", - "description": "An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3750, - "name": "EID3750", - "description": "In a phase 2 clinical trial (NCT00949702) of 132 BRAF mutation positive metastatic melanoma patients treated with vemurafenib monotherapy, patients harboring BRAF V600E (n=123) or V600K (n=9) mutations were associated with a favorable objective response rate (53% per RECIST v1.1 criteria, 70/132), with 6% (8/132) and 47% (62/132) of patients achieving complete response and partial response, respectively.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 60, - "name": "Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.", - "citation": "Trunzer et al., 2013, J. Clin. Oncol.", - "citation_id": "23569304", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23569304", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 5, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3747, - "name": "EID3747", - "description": "In an in vitro study, cell lines (including YUHUY and YUSAC2) expressing BRAF V600E were associated with increased sensitivity to vemurafenib (PLX4032) treatment, as compared to cell lines expressing wild-type BRAF. Sensitive was determined by assessing cellular proliferation, and ERK and MEK phosphorylation.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1482, - "name": "PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.", - "citation": "Halaban et al., 2010, Pigment Cell Melanoma Res", - "citation_id": "20149136", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20149136", - "open_access": true, - "pmc_id": "PMC2848976", - "publication_date": { - "year": 2010, - "month": 4 - }, - "journal": "Pigment Cell Melanoma Res", - "full_journal_title": "Pigment cell & melanoma research", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2123, - "name": "EID2123", - "description": "An inducible BRAF-V600E mouse melanoma model has shown a tight correlation between activated BRAF and disease progression.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1485, - "name": "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.", - "citation": "Hoeflich et al., 2006, Cancer Res.", - "citation_id": "16424035", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16424035", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 1, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 757, - "name": "EID757", - "description": "One patient with BRAF V600E mutated melanoma (with no detected PI3K pathway deregulation) had a partial response on treatment with pictilisib, a PI3K inhibitor, for 9.5 months. Study was a phase-1 with 60 patients enrolled.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 141, - "name": "Pictilisib", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 500, - "name": "First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.", - "citation": "Sarker et al., 2015, Clin. Cancer Res.", - "citation_id": "25370471", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25370471", - "open_access": true, - "pmc_id": "PMC4287394", - "publication_date": { - "year": 2015, - "month": 1, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 8506, - "name": "EID8506", - "description": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Irinotecan, cetuximab and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 250% increased lifespan (ILS) compared to vehicle treated controls. Of the ten treated mice, nine experienced partial response and one experienced a complete response. Compared to all doublet and single agent combinations of vemurafenib, irinotecan, and cetuximab, triplet therapy produced the best TGI and ILS (p<0.05, p <0.0001 for all comparisons).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 108, - "name": "Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.", - "citation": "Yang et al., 2012, Cancer Res.", - "citation_id": "22180495", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22180495", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 2, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7453, - "name": "EID7453", - "description": "In NCI-MATCH trial, patients with advanced solid tumors, lymphoma or multiple myeloma harboring BRAF V600E mutation were treated with dabrafenib and trametinib.\nPatients with melanoma, thyroid carcinoma, colorectal cancer or NSCLC were excluded.\nThe response rate was 100% (4/4) in patients cholangiocarcinoma and 83% (5/6) in patients with low-grade papillary serous adenocarcinoma of the ovary or mucinous-papillary serous adenocarcinoma of the peritoneum.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 2954, - "name": "Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.", - "citation": "April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002", - "citation_id": "172039", - "source_type": "ASCO", - "asco_abstract_id": 3002, - "source_url": "https://meetinglibrary.asco.org/record/172039/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "month": 6 - }, - "journal": "J Clin Oncol 37, 2019 (suppl; abstr 3002)", - "full_journal_title": "Archiv fur experimentelle Veterinarmedizin", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02465060", - "name": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", - "description": "This phase II MATCH trial studies how well treatment that is directed by genetic testing works in patients with solid tumors or lymphomas that have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02465060" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2142, - "name": "EID2142", - "description": "Following treatment with sorafenib, thyroid cancer cell lines with BRAF V600E mutations had severely reduced proliferation rates, but cells with wildtype BRAF were insensitive (P<0.0001).", - "disease": { - "id": 16, - "name": "Thyroid Gland Cancer", - "display_name": "Thyroid Gland Cancer", - "doid": "1781", - "url": "http://www.disease-ontology.org/?id=DOID:1781" - }, - "drugs": [ - { - "id": 6, - "name": "Sorafenib", - "ncit_id": "C61948", - "aliases": [ - "Bay-439006", - "BAY 43-9006", - "BA4 43 9006" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1497, - "name": "BRAF is a therapeutic target in aggressive thyroid carcinoma.", - "citation": "Salvatore et al., 2006, Clin. Cancer Res.", - "citation_id": "16533790", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16533790", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 3, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 7762, - "name": "EID7762", - "description": "In a phase 2 trial, patients with radioiodine refractory papillary thyroid carcinoma harboring BRAF mutation were treated with dabrafenib alone or combination with trametinib. 94% of patients had BRAF V600E.\nThe response rate was 50% (11/22) for dabrafenib and 54% (13/24) for dabrafenb and trametinib combination.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 3096, - "name": "Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.", - "citation": "Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022", - "citation_id": "145877", - "source_type": "ASCO", - "asco_abstract_id": 6022, - "source_url": "https://meetinglibrary.asco.org/record/145877/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017, - "month": 1, - "day": 12 - }, - "journal": "J Clin Oncol 35, 2017 (suppl; abstr 6022)", - "full_journal_title": "Biochimica et biophysica acta", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01723202", - "name": "Dabrafenib With or Without Trametinib in Treating Patients With Recurrent Thyroid Cancer", - "description": "This randomized phase II trial studies how well dabrafenib works with or without trametinib in treating patients with recurrent thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether dabrafenib is more effective when given with or without trametinib in treating thyroid cancer", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01723202" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1421, - "name": "EID1421", - "description": "In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 344 had V600E mutation. 174 patients were treated with vemurafenib and placebo, and 170 were treated with vemurafenib and cobimetinib and tested for progression free survival. 88 of 174 monotherapy group patients had an event with median progression free survival of 6.5 months. In the combination group 58 of 174 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.57 (0.41-0.80).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 963, - "name": "Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.", - "citation": "Larkin et al., 2014, N. Engl. J. Med.", - "citation_id": "25265494", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25265494", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 11, - "day": 13 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01689519", - "name": "A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma", - "description": "To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01689519" - } - ] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 1589, - "name": "EID1589", - "description": "Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months with subsequent disease progression.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1050, - "name": "MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer.", - "citation": "Pietrantonio et al., 2016, Cancer Discov", - "citation_id": "27325282", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27325282", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 6, - "day": 20 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3743, - "name": "EID3743", - "description": "A 51 year old male anaplastic thyroid cancer patient harboring BRAF V600E experienced rapid improvement in response to vemurafenib. The patient was initially treated with paclitaxel and carboplatin but experienced disease progression; subsequently, the patient was treated concurrently with vemurafenib and radiation therapy and achieved near complete regression of metastatic disease.", - "disease": { - "id": 3040, - "name": "Thyroid Gland Anaplastic Carcinoma", - "display_name": "Thyroid Gland Anaplastic Carcinoma", - "doid": "0080522", - "url": "http://www.disease-ontology.org/?id=DOID:0080522" - }, - "drugs": [ - { - "id": 360, - "name": "Radiation Therapy", - "ncit_id": "C15313", - "aliases": [ - "ENERGY_TYPE", - "Radiation Therapy, NOS", - "Therapy, Radiation", - "RT", - "RADIOTHERAPY", - "Radiotherapeutics", - "RADIATION", - "Irradiation", - "Irradiated", - "Irradiate", - "Cancer Radiotherapy" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "submitted", - "type": "evidence", - "source": { - "id": 1948, - "name": "BRAF V600E inhibition in anaplastic thyroid cancer.", - "citation": "Rosove et al., 2013, N. Engl. J. Med.", - "citation_id": "23406047", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23406047", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 2, - "day": 14 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 2137, - "name": "EID2137", - "description": "In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1494, - "name": "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.", - "citation": "Elisei et al., 2008, J. Clin. Endocrinol. Metab.", - "citation_id": "18682506", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18682506", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 10 - }, - "journal": "J. Clin. Endocrinol. Metab.", - "full_journal_title": "The Journal of clinical endocrinology and metabolism", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3762, - "name": "EID3762", - "description": "In a mouse xenograft model, tumors derived from the glioblastoma cell line AM-38 that were treated with vemurafenib had reduced tumor growth and improved survival compared to control treated mice (P=0.018 and 0.0002, respectively). In contrast, mice with wildtype BRAF xenografts did not respond vemurafenib compared to control treatment as measured by tumor size and survival (P=0.179 and P=0.225, respectively ). A malignant astrocytoma cell line that expressed BRAF V600E was more sensitive to growth inhibition by vemurafenib than a cell line with wildtype BRAF (EC50=1.75 vs. 31.2 umol/L).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 348, - "name": "Targeted therapy for BRAFV600E malignant astrocytoma.", - "citation": "Nicolaides et al., 2011, Clin. Cancer Res.", - "citation_id": "22038996", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22038996", - "open_access": true, - "pmc_id": "PMC3638050", - "publication_date": { - "year": 2011, - "month": 12, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - { - "id": 3751, - "name": "EID3751", - "description": "In an in vitro study, BRAF V600E expressing cell lines (COLO205, A375 and COLO829) demonstrated improved sensitivity to vemurafenib treatment, compared to BRAF wild-type expressing cells. Sensitivity was determined by assessing cell proliferation (COLO205, GI50: 0.31uM; A375, GI50: 0.50 uM; COLO829, GI50: 1.7 uM vs. BRAF expressing cells (n=9) GI50: 10-41uM) and ERK phosphorylation.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1952, - "name": "Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.", - "citation": "Tsai et al., 2008, Proc. Natl. Acad. Sci. U.S.A.", - "citation_id": "18287029", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18287029", - "open_access": true, - "pmc_id": "PMC2268581", - "publication_date": { - "year": 2008, - "month": 2, - "day": 26 - }, - "journal": "Proc. Natl. Acad. Sci. U.S.A.", - "full_journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - } - ], - "variant_groups": [], - "assertions": [ - { - "id": 20, - "type": "assertion", - "name": "AID20", - "summary": "BRAF V600E indicates poor prognosis in advanced colorectal cancer", - "description": "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers. \nNCCN Guidelines state that that\nmutations in BRAF are a strong prognostic marker, and recommend BRAF genotyping of either primary or metastatic tumor tissue at diagnosis of stage IV disease.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "evidence_type": "Prognostic", - "evidence_direction": "Supports", - "clinical_significance": "Poor Outcome", - "fda_regulatory_approval": false, - "status": "accepted" - }, - { - "id": 10, - "type": "assertion", - "name": "AID10", - "summary": "BRAF V600E mutant melanoma is sensitive to vemurafenib and cobimetinib combination therapy", - "description": "Vemurafenib and cobimetinib combination is an FDA approved and NCCN Category 1 first line treatment for BRAF V600E mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. NCCN guidelines recommend combination BRAF/MEK inhibitor therapy over BRAF inhibitor monotherapy in this treatment context. Vemurafenib and cobimetinib combination is recommend as Category 2A treatment in second-line or later contexts, and it is recommended to use treatment options different from those used with the patient during first-line therapy. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib).", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - }, - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 12, - "type": "assertion", - "name": "AID12", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "rejected" - }, - { - "id": 7, - "type": "assertion", - "name": "AID7", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy than with BRAF inhibitor alone.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 23, - "type": "assertion", - "name": "AID23", - "summary": "BRAFi + MEKi + EGFRi combination is recommended for BRAF V600E mutation positive colorectal cancer", - "description": "Encorafenib + binimetinib + (Cetuximab or Panitumumab) or Dabrafenib + Trametinib + (Cetuximab or Panitumumab) are recommended as subsequent therapy for BRAF V600E mutation positive colorectal cancer.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 485, - "name": "Binimetinib", - "ncit_id": "C84865", - "aliases": [ - "Mektovi", - "MEK162", - "ARRY-438162", - "ARRY-162" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": false, - "status": "submitted" - } - ], - "variant_aliases": [ - "RS113488022", - "VAL600GLU" - ], - "hgvs_expressions": [ - "NM_004333.4:c.1799T>A", - "NP_004324.2:p.Val600Glu", - "NC_000007.13:g.140453136A>T", - "ENST00000288602.6:c.1799T>A" - ], - "clinvar_entries": [ - "13961", - "376069" - ], - "allele_registry_id": "CA123643" - }, - "ASSERTIONS": [ - { - "id": 20, - "type": "assertion", - "name": "AID20", - "summary": "BRAF V600E indicates poor prognosis in advanced colorectal cancer", - "description": "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers. \nNCCN Guidelines state that that\nmutations in BRAF are a strong prognostic marker, and recommend BRAF genotyping of either primary or metastatic tumor tissue at diagnosis of stage IV disease.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "evidence_type": "Prognostic", - "evidence_direction": "Supports", - "clinical_significance": "Poor Outcome", - "fda_regulatory_approval": false, - "status": "accepted" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID229.json b/analysis/civic/examples/harvester/EID229.json deleted file mode 100644 index da5d0d99..00000000 --- a/analysis/civic/examples/harvester/EID229.json +++ /dev/null @@ -1,4053 +0,0 @@ -{ - "EVIDENCE": { - "id": 229, - "name": "EID229", - "description": "There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - }, - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 162, - "name": "Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21.", - "citation": "Lim et al., 2014, J Thorac Oncol", - "citation_id": "24736073", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24736073", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 4 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [], - "assertions": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ], - "gene_id": 19 - }, - "GENE": { - "id": 19, - "name": "EGFR", - "entrez_id": 1956, - "description": "EGFR is widely recognized for its importance in cancer. Amplification and mutations have been shown to be driving events in many cancer types. Its role in non-small cell lung cancer, glioblastoma and basal-like breast cancers has spurred many research and drug development efforts. Tyrosine kinase inhibitors have shown efficacy in EGFR amplfied tumors, most notably gefitinib and erlotinib. Mutations in EGFR have been shown to confer resistance to these drugs, particularly the variant T790M, which has been functionally characterized as a resistance marker for both of these drugs. The later generation TKI's have seen some success in treating these resistant cases, and targeted sequencing of the EGFR locus has become a common practice in treatment of non-small cell lung cancer. \nOverproduction of ligands is another possible mechanism of activation of EGFR. ERBB ligands include EGF, TGF-a, AREG, EPG, BTC, HB-EGF, EPR and NRG1-4 (for detailed information please refer to the respective ligand section).", - "variants": [ - { - "name": "N771_P772insL", - "id": 3304, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Overexpression", - "id": 193, - "evidence_items": { - "accepted_count": 9, - "rejected_count": 2, - "submitted_count": 3 - } - }, - { - "name": "Exon 4 Deletion", - "id": 252, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Exon 20 Insertion", - "id": 726, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "Exon 18 Overexpression", - "id": 375, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Expression", - "id": 354, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "Wildtype", - "id": 2174, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "L747_T751delinsP", - "id": 1010, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "D770_N771insGL", - "id": 1514, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Amplification", - "id": 190, - "evidence_items": { - "accepted_count": 11, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "A750T", - "id": 2332, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Copy Number Variation", - "id": 191, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Exon 19 Deletion", - "id": 133, - "evidence_items": { - "accepted_count": 16, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "G465E", - "id": 2603, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F404V", - "id": 2617, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F404I", - "id": 2616, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E884K", - "id": 1390, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709Q", - "id": 1413, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D761N", - "id": 1013, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "Mutation", - "id": 442, - "evidence_items": { - "accepted_count": 16, - "rejected_count": 1, - "submitted_count": 3 - } - }, - { - "name": "L858R", - "id": 33, - "evidence_items": { - "accepted_count": 36, - "rejected_count": 1, - "submitted_count": 4 - } - }, - { - "name": "T790M", - "id": 34, - "evidence_items": { - "accepted_count": 30, - "rejected_count": 2, - "submitted_count": 9 - } - }, - { - "name": "Y1092 PHOSPHORYLATION", - "id": 390, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EGFR-RAD51", - "id": 2203, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "R451C", - "id": 454, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "I462R", - "id": 2600, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S464L", - "id": 2601, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S492R", - "id": 453, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I462K", - "id": 2599, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S464T", - "id": 2602, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G465V", - "id": 2604, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K467N", - "id": 2605, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K489Q", - "id": 2606, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719S", - "id": 134, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "K489E", - "id": 2607, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I491K", - "id": 2608, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I491R", - "id": 2609, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S492C", - "id": 2610, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441G", - "id": 2611, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441D", - "id": 2612, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441F", - "id": 2613, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S442R", - "id": 2614, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S442I", - "id": 2615, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T415M", - "id": 2618, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "M766_A767insASV", - "id": 2213, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "delL747_P753insS", - "id": 2215, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D770delinsGY", - "id": 2214, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P772_H773insH", - "id": 2217, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "3' UTR MUTATION", - "id": 253, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "AUTOCRINE ACTIVATION", - "id": 309, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 2, - "submitted_count": 0 - } - }, - { - "name": "C797S", - "id": 415, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "S768N", - "id": 1443, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "Gain-of-function", - "id": 1765, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G465R", - "id": 443, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719", - "id": 718, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S720", - "id": 720, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S752_I759delSPKANKEI", - "id": 891, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L838V", - "id": 1018, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "R108K", - "id": 994, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861Q", - "id": 1020, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "T263P", - "id": 995, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V742A", - "id": 1001, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "E746_T751>I", - "id": 1003, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "E746V", - "id": 1005, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "L747_T751>Q", - "id": 1008, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "E746_S752>D", - "id": 1009, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_T751delLREAT", - "id": 1007, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_P753>Q", - "id": 1011, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "G810S", - "id": 1016, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "R776C", - "id": 1181, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S784F", - "id": 1182, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "N826S", - "id": 1188, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G719D", - "id": 1420, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_S752>A", - "id": 1433, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "H773_V774insH", - "id": 1446, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L747_S752del", - "id": 890, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 7 - } - }, - { - "name": "L747_A750>P", - "id": 1006, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "D770_N771insSVD", - "id": 1445, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "L838P", - "id": 1457, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T847I", - "id": 1463, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861R", - "id": 1477, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E868G", - "id": 1482, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D770_N771insNPG", - "id": 1569, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V774_C775insHV", - "id": 1567, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "W731L", - "id": 1571, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T785A", - "id": 1573, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E734Q", - "id": 1572, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y801H", - "id": 1575, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E709_T710>D", - "id": 1577, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "V769A", - "id": 1578, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "N771>GY", - "id": 1581, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P546S", - "id": 1582, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T854A", - "id": 1467, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P848L", - "id": 1465, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E746_A750>IP", - "id": 1635, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K745_E749delKELRE", - "id": 1638, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "M766_A767insAI", - "id": 1664, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y764_V765insHH", - "id": 1665, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P772_V774insPHV", - "id": 1668, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "P772_H773insYNP", - "id": 1667, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y69FS*11", - "id": 1672, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "N771DELinsVH", - "id": 1662, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V851I", - "id": 1466, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L747_S752delinsQ", - "id": 1580, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Ex19 del L858R", - "id": 1854, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861", - "id": 1866, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V774A", - "id": 1892, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L747P", - "id": 1891, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V774M", - "id": 1894, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V834I", - "id": 1897, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "N842S", - "id": 1899, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "N826Y", - "id": 1896, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "A702S", - "id": 2255, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709K and G719A", - "id": 2256, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Exon 18 deletion", - "id": 2257, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709A and G719C", - "id": 2258, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I744_K745insKIPVAI", - "id": 2259, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S768_D770dup", - "id": 1511, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G598V", - "id": 997, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_P753delinsS", - "id": 1012, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 8 - } - }, - { - "name": "R705K", - "id": 2333, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "RARE EGRF MUT", - "id": 2334, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "RARE Exon 18-21 Mutation", - "id": 1863, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_T751delinsVA", - "id": 1214, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E746_A750del", - "id": 1002, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 19 - } - }, - { - "name": "K467T", - "id": 455, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P753S", - "id": 460, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G724S", - "id": 317, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S768I", - "id": 562, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "E746G", - "id": 724, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L718V and L718Q", - "id": 2997, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "L718Q", - "id": 2999, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "V769_770insASV", - "id": 736, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "D761Y", - "id": 712, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T725M", - "id": 861, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L718V", - "id": 3000, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "A289V", - "id": 996, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_T751delinsA", - "id": 1004, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "R831H", - "id": 1017, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "G719A", - "id": 999, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "A763_Y764insFQEA", - "id": 1515, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "A859T", - "id": 1474, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "A864T", - "id": 1187, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "H773_V774insNPH", - "id": 1513, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "C797Y", - "id": 1574, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "A767_V769dupASV", - "id": 1579, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "K806E", - "id": 1895, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D770_N771insGT", - "id": 1566, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K757R", - "id": 723, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "C797G", - "id": 3003, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L792H", - "id": 3004, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719X", - "id": 2912, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R832L", - "id": 2741, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "M766Q", - "id": 2745, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "VIII", - "id": 312, - "evidence_items": { - "accepted_count": 7, - "rejected_count": 0, - "submitted_count": 2 - } - } - ], - "aliases": [ - "ERRP", - "EGFR", - "mENA", - "PIG61", - "NISBD2", - "HER1", - "ERBB1", - "ERBB" - ], - "type": "gene" - }, - "VARIANT": { - "id": 33, - "entrez_name": "EGFR", - "entrez_id": 1956, - "name": "L858R", - "description": "EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies.", - "gene_id": 19, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 375, - "coordinates": { - "chromosome": "7", - "start": 55259515, - "stop": 55259515, - "reference_bases": "T", - "variant_bases": "G", - "representative_transcript": "ENST00000275493.2", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 229, - "name": "EID229", - "description": "There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 162, - "name": "Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21.", - "citation": "Lim et al., 2014, J Thorac Oncol", - "citation_id": "24736073", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24736073", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 4 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 276, - "name": "EID276", - "description": "Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 4, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 181, - "name": "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.", - "citation": "Paez et al., 2004, Science", - "citation_id": "15118125", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15118125", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2004, - "month": 6, - "day": 4 - }, - "journal": "Science", - "full_journal_title": "Science (New York, N.Y.)", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 879, - "name": "EID879", - "description": "A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001).", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 592, - "name": "Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.", - "citation": "Sequist et al., 2013, J. Clin. Oncol.", - "citation_id": "23816960", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23816960", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 9, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00949650", - "name": "BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation", - "description": "This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00949650" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 883, - "name": "EID883", - "description": "In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 594, - "name": "Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.", - "citation": "Yang et al., 2012, Lancet Oncol.", - "citation_id": "22452895", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22452895", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 5 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00525148", - "name": "LUX Lung 2 Phase II Single Arm BIBW 2992 \"Afatinib\" in NSCLC With EGFR Activating Mutations", - "description": "The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by RECIST criteria in patients with advanced NSCLC Stage IIIB or IV whose tumors harbor activating mutations within exon 18 to exon 21 of the EGFR receptor. Patients progressing or relapsing after one prior cytotoxic chemotherapy regimen as well as chemotherapy na\u00efve patients (only in stage 2) will be allowed to enter into the trial.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00525148" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 885, - "name": "EID885", - "description": "A randomized phase 3 trial (NCT00446225) involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 595, - "name": "Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.", - "citation": "Rosell et al., 2012, Lancet Oncol.", - "citation_id": "22285168", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22285168", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 3 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00446225", - "name": "Phase III Study (Tarceva\u00ae) vs Chemotherapy to Treat Advanced Non-Small Cell Lung Cancer (NSCLC) in Patients With Mutations in the TK Domain of EGFR", - "description": "A Phase III, multicenter, open-label, randomized trial of Erlotinib (Tarceva\u00ae) versus chemotherapy in patients with advanced NSCLC with mutations in the Tyrosine Kinase (TK) domain of the EGFR.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00446225" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 968, - "name": "EID968", - "description": "Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 669, - "name": "In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.", - "citation": "Hirano et al., 2015, Oncotarget", - "citation_id": "26515464", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26515464", - "open_access": true, - "pmc_id": "PMC4770737", - "publication_date": { - "year": 2015, - "month": 11, - "day": 17 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 982, - "name": "EID982", - "description": "Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 679, - "name": "Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.", - "citation": "Wu et al., 2014, Lancet Oncol.", - "citation_id": "24439929", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24439929", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 2 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01121393", - "name": "BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)", - "description": "To investigate the efficacy and safety of BIBW 2992 compared to standard first-line chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01121393" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 275, - "name": "EID275", - "description": "In NSCLC patients treated with EGFR tyrosine kinase inhibitors, the presence of L858R mutation is prognostic for better progression free survival.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 182, - "name": "Clinical predictors of response to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.", - "citation": "Fukihara et al., 2014, Oncology", - "citation_id": "24457318", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24457318", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014 - }, - "journal": "Oncology", - "full_journal_title": "Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 1665, - "name": "EID1665", - "description": "90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and the L858R EGFR mutation was associated with longer time to treatment failure than those with wild-type EGFR (median 9.1 versus 2.1). In multivariate analysis, L858R mutations plus adenocarcinoma was a significant predictive factor for time to treatment failure (HR = 0.1030; P = .0004).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1127, - "name": "Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy.", - "citation": "Yang et al., 2008, J. Clin. Oncol.", - "citation_id": "18509184", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18509184", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 6, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2621, - "name": "EID2621", - "description": "In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1501, - "name": "Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial.", - "citation": "Douillard et al., 2010, J. Clin. Oncol.", - "citation_id": "20038723", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20038723", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 2, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00076388", - "name": "Iressa Versus Docetaxel (Taxotere)", - "description": "The purpose of this study is to compare the effects of ZD1839 or docetaxel in patients with advanced non-small cell lung cancer (NSCLC) that has recurred or progressed after receiving prior treatment with platinum-based chemotherapy.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00076388" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2623, - "name": "EID2623", - "description": "In a phase 3 clinical trial of Japanese NSCLC patients with EGFR mutations (n=230), patients treated with gefitinib were associated with improved progression free survival (10.8 months vs 5.4 months, HR: 0.30, 95% CI: 0.22-0.41, P<0.001), compared to patients treated with carboplatin and paclitaxel combination therapy. The frequency of mutation of exon 19 deletion and L858R was 25.2% (58/230) and 21.3% (49/230), respectively.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1508, - "name": "Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.", - "citation": "Maemondo et al., 2010, N. Engl. J. Med.", - "citation_id": "20573926", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20573926", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 6, - "day": 24 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2624, - "name": "EID2624", - "description": "Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was L858R. The patient was a female former smoker who had lung adenocarcinoma histology, and demonstrated response for 5 months, with overall survival 8 months.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 1, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1509, - "name": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib.", - "citation": "Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A.", - "citation_id": "15329413", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15329413", - "open_access": true, - "pmc_id": "PMC516528", - "publication_date": { - "year": 2004, - "month": 9, - "day": 7 - }, - "journal": "Proc. Natl. Acad. Sci. U.S.A.", - "full_journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2626, - "name": "EID2626", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to lapatinib (IC50: 63nM vs. 534nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 45, - "name": "Lapatinib", - "ncit_id": "C26653", - "aliases": [ - "GW572016", - "GW2016", - "GW 2016", - "GSK572016" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2628, - "name": "EID2628", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated sensitivity to neratinib (IC50: 0.0049 \u03bcmol/L) compared to EGFRwt A549 cells (IC50 > 1 \u03bcmol/L).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 52, - "name": "Neratinib", - "ncit_id": "C49094", - "aliases": [ - "PB-272", - "PB 272", - "HKI-272", - "HKI 272", - "2-Butenamide, N-(4-((3-chloro-4-(2-pyridinylmethoxy)phenyl)amino)-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-, (2E)-", - "(2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1526, - "name": "Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272.", - "citation": "Shimamura et al., 2006, Cancer Res.", - "citation_id": "16818618", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16818618", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 7, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2629, - "name": "EID2629", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to afatinib (IC50: 0.7nM vs. 60nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2630, - "name": "EID2630", - "description": "In a phase 2b/3 study of 585 stage IIIB-IV lung adenocarcinoma patients who had a previous round of EGFR-TKI treatment, archival material was available for 141 patients. EGFR mutational analysis revealed that 96 tumors had an EGFR mutation, of which 76 (79%) were positive for either L858R or a deletion in exon 19. These mutations were associated with improved progression-free survival (median 3.3 months vs 1.0 month ; HR:0.51, 95% CI:0.31-0.85, P<0.009) compared to placebo control.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1510, - "name": "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.", - "citation": "Miller et al., 2012, Lancet Oncol.", - "citation_id": "22452896", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22452896", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 5 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00656136", - "name": "BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)", - "description": "This randomized, double-blind, multi-center Phase IIb/III trial will be performed in patients with NSCLC who have received previous treatment with at least one but not more than two lines of cytotoxic chemotherapy (one line must have been a platinum-containing regimen) and either gefitinib or erlotinib for a period of at least 12 weeks and then progressed. The primary objective of this randomized trial is to determine the efficacy of BIBW 2992 as a single agent (Arm A) as compared to a matching placebo (Arm B) in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00656136" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2631, - "name": "EID2631", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to canertinib (IC50: 1nM vs. 198nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 465, - "name": "Canertinib", - "ncit_id": "C77588", - "aliases": [ - "N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide", - "2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2633, - "name": "EID2633", - "description": "EGFR L858R mutation has been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib.In an in vitro study using PC9 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. PC9 cells demonstrated an increased sensitivity to gefitinib (IC50: 11.0-12.0 nmol/L vs 61.0 nmol/L) compared to NCI-H2073 cells (EGFR wild type).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 427, - "name": "Durvalumab", - "ncit_id": "C103194", - "aliases": [ - "MEDI4736", - "MEDI-4736", - "Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide With Human Monoclonal MEDI4736 Kappa-chain, Dimer", - "Imfinzi" - ] - } - ], - "rating": 1, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2634, - "name": "EID2634", - "description": "In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1513, - "name": "First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.", - "citation": "Han et al., 2012, J. Clin. Oncol.", - "citation_id": "22370314", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22370314", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 4, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4265, - "name": "EID4265", - "description": "MCF-7 cells were transduced with YFP tagged EGFR with E746_A750delELREA mutation, or YFP EGFR wildtype, and stained for ectopic YFP EGFR and phospho-Akt as a readout for EGFR pathway activity. Increased p-Akt stain was seen with ectopic mutant EGFR over wildtype cells. Parallel erlotinib incubations of cells with wildtype EGFR induced recompartmentalization of ectopic EGFR protien only at high concentration (10uM). Addition of erlotinib to mutant EGFR cell incubations reduced p-Akt signal and induced recompartmentalization of ectopic EGFR protien at considerably lower conecntration (100 nM) erlotinib. These results indicate the EGFR L858R variant as a growth pathway driver targetable by erlotinib.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1991, - "name": "Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.", - "citation": "de Gunst et al., 2007, Mol. Cancer", - "citation_id": "17877814", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17877814", - "open_access": true, - "pmc_id": "PMC2064929", - "publication_date": { - "year": 2007, - "month": 9, - "day": 18 - }, - "journal": "Mol. Cancer", - "full_journal_title": "Molecular cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4284, - "name": "EID4284", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to erlotinib (IC50: 40nM vs. 110nM) compared to EGFR wild type cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4285, - "name": "EID4285", - "description": "In an in vitro study, a MCF-7 cell line expressing EGFR L858R mutation demonstrated sensitivity to erlotinib treatment, compared to MCF-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing YFP signal-EGFR relocation.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1993, - "name": "Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry.", - "citation": "Harada et al., 2011, Oncogene", - "citation_id": "21132006", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21132006", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 4, - "day": 14 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4286, - "name": "EID4286", - "description": "In an in vitro study, Ba/F3 and NCI-H3255 cell lines expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment (IC50=0.006 and 0.068 \u00b5M). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1230, - "name": "Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.", - "citation": "Yasuda et al., 2013, Sci Transl Med", - "citation_id": "24353160", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24353160", - "open_access": true, - "pmc_id": "PMC3954775", - "publication_date": { - "year": 2013, - "month": 12, - "day": 18 - }, - "journal": "Sci Transl Med", - "full_journal_title": "Science translational medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4287, - "name": "EID4287", - "description": "In an in vitro study, CHO and NCI-H3255 cells expressing EGFR L858R mutation were associated with sensitivity to erlotinib treatment. Sensitivity was determined by assessing cell density.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2070, - "name": "Differential protein stability of EGFR mutants determines responsiveness to tyrosine kinase inhibitors.", - "citation": "Ray et al., 2016, Oncotarget", - "citation_id": "27612423", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27612423", - "open_access": true, - "pmc_id": "PMC5356576", - "publication_date": { - "year": 2016, - "month": 10, - "day": 18 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4288, - "name": "EID4288", - "description": "This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One patient was biopsied twice following crizotinib progression and once pre-treatment. This patient was a 27 year old female with one pack year who experienced partial response on crizotinib as 4th line therapy. The patient's pre-crizotinib biopsy was ALK+ and lacked the EGFR mutation. A biopsy taken after 63 days on crizotinib showed EGFR L858R mutation and lacked ALK gene rearrangement by FISH (ALK Loss). Of note, a second post-treatment biopsy (after 113 on crizotinib) showed ALK rearrangement but lacked EGFR mutation. The authors interpreted the emergence of an ALK negative tumor (first post-critozitinib biopsy) as evidence of a separate oncogenic driver (EGFR L858R).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 507, - "name": "Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.", - "citation": "Doebele et al., 2012, Clin. Cancer Res.", - "citation_id": "22235099", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22235099", - "open_access": true, - "pmc_id": "PMC3311875", - "publication_date": { - "year": 2012, - "month": 3, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4290, - "name": "EID4290", - "description": "In a prospective study of 46 Caucasian, advanced lung adenocarcinoma patients harboring EGFR mutations, first-line erlotinib treatment was assessed. Average PFS and OS for these 46 patients was 11 months (95% CI: 9.7-12.3 months) and 23 months (95% CI: 21.3-28.6+ months), respectively. A PFS rate of 81% at three months met the primary endpoint of presumed superiority over chemotherapy. Clinical benefit (CR+PR+SD) rate was 81%. Fifteen patients harbored EGFR L858R mutations, which was the only mutation found in exon 21. The authors note similar response profiles for exon 19 (27/46) and exon 21 mutations (15/46) to the overall population.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2067, - "name": "Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT).", - "citation": "De Gr\u00e8ve et al., 2016, PLoS ONE", - "citation_id": "27032107", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27032107", - "open_access": true, - "pmc_id": "PMC4816447", - "publication_date": { - "year": 2016 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00339586", - "name": "First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene", - "description": "Current chemotherapy for advanced non-small cell lung cancer, not amenable for curative local treatment (surgery or chemoradiotherapy), has a modest life-prolonging effect and can improve quality of life. There is however no potential for long-term cure for these patients. Chemotherapy also produces variable and often significant toxicity. Current retrospective evidence suggests that significant clinical responses can be obtained when patients whose cancer cells have an EGFR TKD mutation are treated with an EGFR TKI. The ease of administration and toxicity profile of TKI compare favourably with that of chemotherapy, even single agents such as for example gemcitabine The present study will establish the clinical benefit rate of TKI as a first line treatment in patients with EGFR mutations and thus estimate the proportion of patients who might benefit for a prolonged period from a treatment with a modest toxicity profile.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00339586" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4291, - "name": "EID4291", - "description": "In an in vitro study, Ba/F3 cell line expressing EGFR L858R was associated with sensitivity to erlotinib treatment (IC50 26.9 \u00b1 12.4). Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation, and EGFR auto-phosphorylation.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2086, - "name": "EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.", - "citation": "Konduri et al., 2016, Cancer Discov", - "citation_id": "27102076", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27102076", - "open_access": true, - "pmc_id": "PMC4893907", - "publication_date": { - "year": 2016 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4292, - "name": "EID4292", - "description": "In an in vitro study, Ba/F3 cell line expressing EGFR L858R did not show sensitivity to cetuximab treatment, while cells expressing EGFR-RAD51 fusion were sensitive. Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation and EGFR auto-phosphorylation.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2086, - "name": "EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.", - "citation": "Konduri et al., 2016, Cancer Discov", - "citation_id": "27102076", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27102076", - "open_access": true, - "pmc_id": "PMC4893907", - "publication_date": { - "year": 2016 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4293, - "name": "EID4293", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to erlotinib (IC50: 8 and 11 nM) compared to EGFRwt NCI-H2073 cells (IC50: 108 nM; 95%CI 52-223 nM).", - "disease": { - "id": 174, - "name": "Lung Small Cell Carcinoma", - "display_name": "Lung Small Cell Carcinoma", - "doid": "5409", - "url": "http://www.disease-ontology.org/?id=DOID:5409" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4295, - "name": "EID4295", - "description": "In an in vitro study, a Ba/F3 cell line expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0\u201310 uM).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1608, - "name": "Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.", - "citation": "Lee et al., 2006, PLoS Med.", - "citation_id": "17177598", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17177598", - "open_access": true, - "pmc_id": "PMC1702556", - "publication_date": { - "year": 2006, - "month": 12 - }, - "journal": "PLoS Med.", - "full_journal_title": "PLoS medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2994, - "name": "EID2994", - "description": "On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1724, - "name": "U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations.", - "citation": "Khozin et al., 2014, Oncologist", - "citation_id": "24868098", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24868098", - "open_access": true, - "pmc_id": "PMC4077454", - "publication_date": { - "year": 2014, - "month": 7 - }, - "journal": "Oncologist", - "full_journal_title": "The oncologist", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2997, - "name": "EID2997", - "description": "Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1725, - "name": "Afatinib: first global approval.", - "citation": "Dungo et al., 2013, Drugs", - "citation_id": "23982599", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23982599", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 9 - }, - "journal": "Drugs", - "full_journal_title": "Drugs", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4860, - "name": "EID4860", - "description": "The authors pooled patients with exon 19 deletion and L858R EGFR (Exon 21) mutations from both studies (The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)) to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. For those (exon19/21), the median PFS was 14.6 months with dacomitinib and 9.6 months with erlotinib The median survival was 26.6 months with dacomitinib versus 23.2 months with erlotinib.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 44, - "name": "Dacomitinib", - "ncit_id": "C53398", - "aliases": [ - "Vizimpro", - "PF-299804", - "PF-00299804-03", - "PF-00299804", - "EGFR Inhibitor PF-00299804", - "(2E)-N-(4-((3-Chloro-4-Fluorophenyl)Amino)-7-Methoxyquinazolin-6-yl)-4-Piperidin-1-ylbut-2-Enamide" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2158, - "name": "Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.", - "citation": "Ramalingam et al., 2016, Ann. Oncol.", - "citation_id": "26768165", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26768165", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 3 - }, - "journal": "Ann. Oncol.", - "full_journal_title": "Annals of oncology : official journal of the European Society for Medical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01360554", - "name": "ARCHER 1009 : A Study Of Dacomitinib (PF-00299804) Vs. Erlotinib In The Treatment Of Advanced Non-Small Cell Lung Cancer", - "description": "This is a multinational, multicenter, randomized,double-blinded, Phase 3 study comparing the efficacy and safety of treatment with PF-00299804 to treatment with erlotinib in patients with advanced non-small cell lung cancer, previously treated with at least one prior regimen. Analyses of primary objective (Progression Free Survival) will be done in two co-primary populations as defined in the protocol.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01360554" - }, - { - "nct_id": "NCT00769067", - "name": "A Randomized Trial Of PF-00299804 Taken Orally Versus Erlotinib Taken Orally For Treatment Of Advanced Non-Small Cell Lung Cancer That Has Progressed After One Or Two Prior Chemotherapy Regimen", - "description": "This study will compare PF-00299804 given orally on continuous schedule to the approved drug, erlotinib, in patients whose non-small cell lung cancer has progressed after chemotherapy; patients will be randomized to receive one of these drugs, and followed for efficacy and tolerance of each.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00769067" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2632, - "name": "EID2632", - "description": "In a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma), EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib. Two patients had the del L858R mutation. One patient was a male former smoker who demonstrated response for 3 months with overall survival of 3.5 months, and the other patient was a female never smoker who had response for 6 months and overall survival of 17+ months as the patient was alive at study end.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1509, - "name": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib.", - "citation": "Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A.", - "citation_id": "15329413", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15329413", - "open_access": true, - "pmc_id": "PMC516528", - "publication_date": { - "year": 2004, - "month": 9, - "day": 7 - }, - "journal": "Proc. Natl. Acad. Sci. U.S.A.", - "full_journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 3811, - "name": "EID3811", - "description": "EGFR L858R was expressed in Ba/F3 cells which do not contain endogenous EGFR, and conferred growth factor independance to the cells. Cells were plated and treated with 1st generation EGFR inhibitors Gefitinib, Erlotinib, or the the tool compound AEE788, and IC50 values were measured. L858R EGFR cells had very low IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib=12, Erlotinib=6, AEE788=6), indicating sensitivity to all three constructs.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - }, - { - "id": 90, - "name": "Multikinase Inhibitor AEE788", - "ncit_id": "C48369", - "aliases": [ - "AEE788", - "AEE-788", - "AEE 788" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1528, - "name": "Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy.", - "citation": "Kancha et al., 2009, Clin. Cancer Res.", - "citation_id": "19147750", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19147750", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 1, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 5922, - "name": "EID5922", - "description": "In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR L858R demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR \n expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 2081, - "name": "Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma.", - "citation": "Foster et al., 2010, World J Surg Oncol", - "citation_id": "20942962", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20942962", - "open_access": true, - "pmc_id": "PMC2970593", - "publication_date": { - "year": 2010, - "month": 10, - "day": 13 - }, - "journal": "World J Surg Oncol", - "full_journal_title": "World journal of surgical oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 6183, - "name": "EID6183", - "description": "In a Japanese Phase III clinical trial, noninferiority of Gefitinib as compared to Erlotinib was assessed in 561 postoperative recurrent or stage IIIb/VI patients who had undergone prior chemotherapy treatment but no tyrosine kinase inhibitor therapy. In a subset of patients with sole EGFR L858R, there was an insignificant difference between the objective response and disease control rates for patients treated with erlotinib (N=67) and gefitinib (N=78). Progression free survival was also not significantly different and did not meet the noninferiority endpoint with Gefitinib and Erlotinib arms at 8.1 and 8.5 months, respectively (HR, 0.938; 95% CI, 0.675 to 1.304; P = .704).", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2478, - "name": "Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L.", - "citation": "Urata et al., 2016, J. Clin. Oncol.", - "citation_id": "27022112", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27022112", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2627, - "name": "EID2627", - "description": "In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to Dacomitinib (IC50: 0.007umol/L vs. >10umol/L) compared to wildtype EGFR cells or compared to reversible TKI drug gefitinib (IC50: 0.075umol/L vs. wild-type >10umol/L).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 44, - "name": "Dacomitinib", - "ncit_id": "C53398", - "aliases": [ - "Vizimpro", - "PF-299804", - "PF-00299804-03", - "PF-00299804", - "EGFR Inhibitor PF-00299804", - "(2E)-N-(4-((3-Chloro-4-Fluorophenyl)Amino)-7-Methoxyquinazolin-6-yl)-4-Piperidin-1-ylbut-2-Enamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1515, - "name": "PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.", - "citation": "Engelman et al., 2007, Cancer Res.", - "citation_id": "18089823", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18089823", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2007, - "month": 12, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 8053, - "name": "EID8053", - "description": "A 62 year old patient with 4 pack-year smoking history with back and flank pain was found to have metastatic lung adenocarcinoma by CT and MRI. Targeted NGS sequencing discovered an EGFR L858R mutation and the patient started 80mg osimertinib treatment with excellent response of all disease sites, including brain metastases. The patient had continued response until 8.5 months after treatment initiation when a new liver lesion was found. NGS sequencing of a repeat biopsy detected the original EGFR L858R mutation as well as L718V and L718Q mutations. Afatinib treatment led to a partial response for 4.5 months, at which time disease progression occurred. Biopsy of a progressing liver lesion showed acquired EGFR T790M mutation as well as increase and decrease of L718V and L718Q mutation frequencies, respectively.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 187, - "name": "Osimertinib", - "ncit_id": "C116377", - "aliases": [ - "Tagrisso", - "Mereletinib", - "AZD9291", - "AZD-9291", - "2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3253, - "name": "Drug sensitivity and allele-specificity of first-line osimertinib resistance EGFR mutations.", - "citation": "Starrett et al., 2020, Cancer Res.", - "citation_id": "32193290", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/32193290", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2020, - "month": 3, - "day": 19 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4294, - "name": "EID4294", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to AZD9291 (IC50: 60 and 49 nM) compared to EGFRwt NCI-H2073 cells (IC50: 1865 nM; 95%CI 872-3988 nM). In vivo experiments with NCI-H3255 xenograft models showed drastic tumour volume reduction upon treatment with 5mg/kg/day AZD9291.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 187, - "name": "Osimertinib", - "ncit_id": "C116377", - "aliases": [ - "Tagrisso", - "Mereletinib", - "AZD9291", - "AZD-9291", - "2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 347, - "name": "EID347", - "description": "Median survival of patients with EGFR L858R mutation is better than those with wild type EGFR.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Better Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 213, - "name": "Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer.", - "citation": "Douillard et al., 2014, J Thorac Oncol", - "citation_id": "24662454", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24662454", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 5 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - } - ], - "variant_groups": [], - "assertions": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 6, - "type": "assertion", - "name": "AID6", - "summary": "EGFR L858R positive NSCLC is sensitive to afatinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis, including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor afatinib is FDA approved, and is recommended (category 1) by NCCN guidelines along with erlotinib, gefitinib and osimertinib as first line systemic therapy in NSCLC with sensitizing EGFR mutation.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ], - "variant_aliases": [ - "LEU858ARG", - "RS121434568" - ], - "hgvs_expressions": [ - "NC_000007.13:g.55259515T>G", - "NM_005228.4:c.2573T>G", - "ENST00000275493.2:c.2573T>G", - "NP_005219.2:p.Leu858Arg" - ], - "clinvar_entries": [ - "376280", - "16609", - "376282" - ], - "allele_registry_id": "CA126713" - }, - "ASSERTIONS": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID262.json b/analysis/civic/examples/harvester/EID262.json deleted file mode 100644 index cf59a4fa..00000000 --- a/analysis/civic/examples/harvester/EID262.json +++ /dev/null @@ -1,1520 +0,0 @@ -{ - "EVIDENCE": { - "id": 262, - "name": "EID262", - "description": "A 28 year-old patient with non-small cell lung cancer that failed conventional therapy was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 166, - "name": "EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.", - "citation": "Choi et al., 2010, N. Engl. J. Med.", - "citation_id": "20979473", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20979473", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 10, - "day": 28 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [], - "assertions": [ - { - "id": 3, - "type": "assertion", - "name": "AID3", - "summary": "Lung adenocarcinoma positive for ALK-FUSIONS have been found to be sensitive to crizotinib treatment", - "description": "ALK-FUSIONS induce an active form of the receptor tyrosine kinase ALK. ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation. the ALK inhibitor crizotinib was effective in lung cancer patients with ALK fusions and was granted accelerated FDA approval in 2011. The Vysis break-apart FISH assay is an FDA approved test for the presence of ALK fusion. NCCN guideline version 9.2017 lists crizotinib as approved first-line NSCLC treatment in the presence of ALK fusions but now lists alectinib as preferred first-line therapy.", - "gene": { - "name": "ALK", - "id": 1 - }, - "variant": { - "name": "ALK FUSIONS", - "id": 499 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ], - "gene_id": 1 - }, - "GENE": { - "id": 1, - "name": "ALK", - "entrez_id": 238, - "description": "ALK amplifications, fusions and mutations have been shown to be driving events in non-small cell lung cancer. While crizontinib has demonstrated efficacy in treating the amplification, mutations in ALK have been shown to confer resistance to current tyrosine kinase inhibitors. Second-generation TKI's have seen varied success in treating these resistant cases, and the HSP90 inhibitor 17-AAG has been shown to be cytostatic in ALK-altered cell lines.", - "variants": [ - { - "name": "ALK FUSIONS", - "id": 499, - "evidence_items": { - "accepted_count": 31, - "rejected_count": 2, - "submitted_count": 10 - } - }, - { - "name": "EML6-ALK e1-e20 and FBXO11-ALK e1-e20", - "id": 2750, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK e6-e20", - "id": 503, - "evidence_items": { - "accepted_count": 7, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK e2-e20", - "id": 501, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK e20-e20", - "id": 500, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK e6-e19 G1269A and AMPLIFICATION", - "id": 3204, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F1245C", - "id": 549, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "STRN-ALK", - "id": 2218, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "ALTERNATIVE TRANSCRIPT (ATI)", - "id": 839, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "MUTATION", - "id": 512, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "NPM-ALK", - "id": 513, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "RANBP2-ALK", - "id": 514, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "DEL4-11", - "id": 550, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK I1171S", - "id": 589, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "CLTC-ALK", - "id": 520, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "F1174C", - "id": 1492, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L1196Q", - "id": 1553, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK", - "id": 5, - "evidence_items": { - "accepted_count": 7, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F1174L", - "id": 8, - "evidence_items": { - "accepted_count": 9, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "EML4-ALK L1196M", - "id": 7, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 11 - } - }, - { - "name": "EML4-ALK S1206Y", - "id": 172, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "EML4-ALK L1152R", - "id": 307, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "ALK FUSION G1269A", - "id": 552, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "ALK FUSION G1202R", - "id": 171, - "evidence_items": { - "accepted_count": 6, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "ALK FUSION F1245C", - "id": 551, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK T1151INST", - "id": 173, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "HIP1-ALK I1171N", - "id": 588, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "ALK FUSION I1171", - "id": 527, - "evidence_items": { - "accepted_count": 7, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "EML4-ALK V1180L", - "id": 528, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK G1269A", - "id": 308, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "L1198F", - "id": 1275, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 1 - } - }, - { - "name": "F1174V", - "id": 1505, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L1152P", - "id": 1554, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L1198P", - "id": 1556, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R1192P", - "id": 1661, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 2 - } - }, - { - "name": "R1275Q", - "id": 9, - "evidence_items": { - "accepted_count": 6, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "F1245V", - "id": 1295, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "OVEREXPRESSION", - "id": 2635, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R214H", - "id": 1683, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T1151M", - "id": 1493, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EXPRESSION", - "id": 2914, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "ALK FUSION L1196M", - "id": 2819, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G1128A", - "id": 2798, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK G1202del", - "id": 2813, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK L1198F", - "id": 2816, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK G1202R and L1198F", - "id": 2811, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK L1196M and L1198F", - "id": 2810, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK G1202R and L1196M", - "id": 2809, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "CAD-ALK", - "id": 2769, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK C1156Y-L1198F", - "id": 352, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "EML4-ALK and AMPLIFICATION", - "id": 170, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EML4-ALK C1156Y", - "id": 6, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 2, - "submitted_count": 7 - } - } - ], - "aliases": [ - "ALK", - "NBLST3", - "CD246" - ], - "type": "gene" - }, - "VARIANT": { - "id": 5, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK", - "description": "The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 38, - "coordinates": { - "chromosome": "2", - "start": 42396490, - "stop": 42522656, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000318522.5", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 1121, - "name": "EID1121", - "description": "A 39-year-old man presented was observed to have lung acinar adenocarcinoma. Treatment with chemotherapy produced no remarkable response. A EGFR L858R point mutation was observed; the patient was therefore treated with erlotinib, but the disease progressed after 30 days. A second biopsy identified a EML4-ALK fusion, which may explain the therapeutic resistance.", - "disease": { - "id": 1594, - "name": "Lung Acinar Adenocarcinoma", - "display_name": "Lung Acinar Adenocarcinoma", - "doid": "6482", - "url": "http://www.disease-ontology.org/?id=DOID:6482" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 776, - "name": "A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene.", - "citation": "Tanaka et al., 2012, BMC Cancer", - "citation_id": "23181703", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23181703", - "open_access": true, - "pmc_id": "PMC3515412", - "publication_date": { - "year": 2012 - }, - "journal": "BMC Cancer", - "full_journal_title": "BMC cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 1188, - "name": "EID1188", - "description": "A retroviral cDNA expression library was constructed using a lung adenocarcinoma specimen from a 67 year old NSCLC patient, and transfected into mouse 3T3 fibroblasts which were assessed for transformed foci. Analysis of clones from one transformed focus yielded a novel fusion. This fusion generated a protein with N-terminal consisting of EML4 exons 1-13 and C-terminal consisting of ALK exons 20-29, which comprise the intracellular kinase domain of ALK. In subsequent experiments using EML4-ALK or altered versions, the transforming potential of EML4-ALK was found to be dependent on a functional ALK kinase activity as well as the EML4 basic domain, which was shown to have an important role in EML4-ALK dimer formation. BA/F3 cells expressing EML4-ALK were able to grow independently of IL3 addition, but addition of ALK inhibitor WHI-P154 induced cell death and inhibited tyrosine phosphorylation of EML4-ALK. These results indicated that EML4-ALK may be a driver mutation in NSCLC, and a target for ALK inhibitor treatment.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 301, - "name": "WHI-P154", - "ncit_id": null, - "aliases": [] - } - ], - "rating": 5, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 820, - "name": "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.", - "citation": "Soda et al., 2007, Nature", - "citation_id": "17625570", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17625570", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2007, - "month": 8, - "day": 2 - }, - "journal": "Nature", - "full_journal_title": "Nature", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 1203, - "name": "EID1203", - "description": "In preclinical work using H3122 NSCLC cells which contain the EML4-ALK variant 1, administration of the Hsp90 inhibitor IPI-504 caused marked decrease of EML4-ALK protein levels at concentrations lower than those used to knock down protein levels of drivers such as HER2 or EGFR in other cell lines, making it the most sensitive Hsp90 client protein the authors had encountered. IPI-504 treatment caused regression of H3122 tumors in nude mice, whereas Hsp90 inhibitors usually only cause growth inhibition in these models. Combined treatment of these mice with IPI-504 and crizotinib caused an even stronger tumor regression.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 303, - "name": "Retaspimycin Hydrochloride", - "ncit_id": "C48401", - "aliases": [ - "IPI-504", - "Geldanamycin, 18,21-didehydro-17-demethoxy-18,21-dideoxo-18,21-dihydroxy-17-(2-propenylamino)-, Monohydrochloride", - "17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride" - ] - }, - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 4, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 832, - "name": "The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models.", - "citation": "Normant et al., 2011, Oncogene", - "citation_id": "21258415", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21258415", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 6, - "day": 2 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 1206, - "name": "EID1206", - "description": "Transduction of Ba/F3 cells with EML4-ALK variant 1 causes IL3 independent growth. Incubation of EML4-ALK variant 1 transduced Ba/F3 cells with Hsp90 inhibitor 17-DMAG caused cell death that was reversible with IL3 addition, suggesting that 17-DMAG was effecting the EML4-ALK driver of IL3-independant proliferation, and that EML4-ALK variant 1 is a client protein of Hsp90. The degree of Hsp90 dependence, and targetability of EML4-ALK for Hsp90 inhibition, may vary among ALK fusion variants. Addition of crizotinib to 17-DMAG caused synergistic death effects, suggesting potential clinical benefit for this inhibitor combination in targeting EML4-ALK variant 1.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 304, - "name": "Alvespimycin", - "ncit_id": "C38142", - "aliases": [ - "Geldanamycin,17-demethoxy-17-((2-(dimethylamino)ethyl)amino)-", - "17-DMAG", - "17-dimethylaminoethylamino-17-demethoxygeldanamycin", - "17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin" - ] - }, - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 826, - "name": "Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.", - "citation": "Heuckmann et al., 2012, Clin. Cancer Res.", - "citation_id": "22912387", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22912387", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 9, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 1207, - "name": "EID1207", - "description": "In the PROFILE 1001 study of crizotinib in 82 patients with ALK-rearranged NSCLC, 31 patients with sufficient tumor material were tested using RT-PCR for the presence of certain EML4-ALK variants. 13/31 tested patients had the EML4-ALK variant 1. Of these, 12/13 had a partial response, and 1 had stable disease. This response rate of 92% is in contrast to the 57% response rate in the overall patient population, but the numbers of patients with specific EML4-ALK breakpoints were insufficient to correlate with patient response rate.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 819, - "name": "Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.", - "citation": "Kwak et al., 2010, N. Engl. J. Med.", - "citation_id": "20979469", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20979469", - "open_access": true, - "pmc_id": "PMC3014291", - "publication_date": { - "year": 2010, - "month": 10, - "day": 28 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00585195", - "name": "A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer", - "description": "PF-02341066 may work in cancer by blocking the cell growth, migration and invasion of tumor cells. PF-02341066 is a new class of drugs called c-Met/Hepatocyte growth factor receptor tyrosine kinase inhibitors. This compound is also an inhibitor of the anaplastic lymphoma kinase (called ALK) tyrosine kinase and ROS receptor tyrosine kinases. This research study is the first time PF-02341066 will be given to people. PF-02341066 is taken by mouth daily.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00585195" - } - ] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 1332, - "name": "EID1332", - "description": "EML4-ALK variant 1 containing H-3122 NSCLC cells were treated with second generation ALK inhibitor PF-06463922. PF-06463922 was 125x more potent at reducing cell viability than crizotinib. Control neuroblastoma cell lines with wild-type ALK did not show inhibition below 3800 nM with either drug. At values of 10 and 100 nM, PF-06463922 showed increased ability to inhibit ALK 1278 tyrosine phosphorylation in H3122 cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 241, - "name": "Lorlatinib", - "ncit_id": "C113655", - "aliases": [ - "PF-06463922", - "Lorbrena", - "7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile", - "2H-4,8-Methenopyrazolo(4,3-H)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10R)-" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 919, - "name": "The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma.", - "citation": "Infarinato et al., 2016, Cancer Discov", - "citation_id": "26554404", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26554404", - "open_access": true, - "pmc_id": "PMC4707106", - "publication_date": { - "year": 2016, - "month": 1 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 7482, - "name": "EID7482", - "description": "One patient with colorectal cancer harboring MSI-High and EML4-ALK rearrangement received Nivolumab and achieved a durable response.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 137, - "name": "Nivolumab", - "ncit_id": "C68814", - "aliases": [ - "Opdivo", - "ONO-4538", - "NIVO", - "MDX-1106", - "BMS-936558" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 2971, - "name": "ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.", - "citation": "Pietrantonio et al., 2017, J. Natl. Cancer Inst.", - "citation_id": "29370427", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29370427", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017, - "day": 1 - }, - "journal": "J. Natl. Cancer Inst.", - "full_journal_title": "Journal of the National Cancer Institute", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - }, - { - "id": 262, - "name": "EID262", - "description": "A 28 year-old patient with non-small cell lung cancer that failed conventional therapy was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 166, - "name": "EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.", - "citation": "Choi et al., 2010, N. Engl. J. Med.", - "citation_id": "20979473", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20979473", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 10, - "day": 28 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 5, - "phenotypes": [] - } - ], - "variant_groups": [ - { - "id": 11, - "name": "ALK Fusions", - "description": "ALK fusion positive non-small cell lung cancer (NSCLC) is treated as its own subset of NSCLC. Many ALK fusions that have been seen as recurrent in cancer serve to increase the activity of the ALK oncogene relative to normal cells. While EML4 is the most common fusion partner, other 5' partners have been observed. The EML4-ALK fusion has shown sensitivity to targeted tyrosine kinase inhibitors such as crizotinib. ", - "variants": [ - { - "id": 5, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK", - "description": "The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 38, - "coordinates": { - "chromosome": "2", - "start": 42396490, - "stop": 42522656, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000318522.5", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 6, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK C1156Y", - "description": "In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, C1156Y has been shown to confer resistance to crizotinib. Case reports indicate that secondary mutations can modulate drug sensitivity. EML4-ALK C1156Y/L1196M maintained crizotinib resistance while the lorlatinib resistant combination EML4-ALK C1156Y/L1198F re-sensitized the tumor to crizotinib treatment.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - }, - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 29, - "coordinates": { - "chromosome": "2", - "start": 29445258, - "stop": 29445258, - "reference_bases": "C", - "variant_bases": "T", - "representative_transcript": "ENST00000389048.3", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 7, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK L1196M", - "description": "In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, L1196M has been shown to confer resistance to crizotinib. This was also true in a patient with both EML4-ALK C1156Y & L1196M.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - }, - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 21, - "coordinates": { - "chromosome": "2", - "start": 29443631, - "stop": 29443631, - "reference_bases": "G", - "variant_bases": "T", - "representative_transcript": "ENST00000389048.3", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 499, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "ALK FUSIONS", - "description": "Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. \n\nIn a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. \n\nDue to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib \u2013 a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. \n\nALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 648, - "coordinates": { - "chromosome": "2", - "start": 29415640, - "stop": 29446394, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000389048.3", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 500, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK e20-e20", - "description": "EML4-ALK variant 2 consists of a fusion of the ALK kinase domain (exons 20-29) with EML4 exons 1-20. Variant 2 has cytoplasmic distribution and makes up ~10% of EML4-ALK fusions found in NSCLC,. Although the specific variant is not consistently reported, single cases demonstrating response to crizotinib treatment in NSCLC and a differentiated malignant neoplasm of unknown origin have been reported. In vitro, this variant has shown greater sensitivity to ALK inhibition with TAE684 and crizotinib than the EML4-ALK variants 1 (E13;A20), 3a (E6;A20) and 3b (E6ins33;A20). The variant was reported to be less stable in cells than other variants, and may be a client protein of Hsp90. Along these lines the variant has shown preclinical sensitivity to Hsp90 inhibition.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 16.5, - "coordinates": { - "chromosome": "2", - "start": 42396490, - "stop": 42552694, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000318522.5", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 501, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK e2-e20", - "description": "", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 1.75, - "coordinates": { - "chromosome": "2", - "start": 42396490, - "stop": 42472827, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000318522.5", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 503, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "EML4-ALK e6-e20", - "description": "The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition.", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 25, - "coordinates": { - "chromosome": "2", - "start": 42396490, - "stop": 42491871, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000318522.5", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 513, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "NPM-ALK", - "description": "", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 27, - "coordinates": { - "chromosome": "5", - "start": 170814120, - "stop": 170818803, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000517671.1", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 514, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "RANBP2-ALK", - "description": "", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 10, - "coordinates": { - "chromosome": "2", - "start": 109335937, - "stop": 109375004, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000283195.6", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 520, - "entrez_name": "ALK", - "entrez_id": 238, - "name": "CLTC-ALK", - "description": "The t(2;17)(p23;q23) translocation results in the CLTC-ALK fusion protein, the most common ALK fusion observed in diffuse large B cell lymphoma (DLBCL). ALK-rearranged DLBCL is less responsive to CHOP chemotherapy. Preclinical work indicates that CLTC-ALK DLBCL is responsive to ALK inhibition in cell lines and mouse models, and two case studies show short response followed by progression when heavily pretreated and advanced ALK-positive DLBCL is treated with crizotinib (one case CLTC-ALK, one case an unknown ALK fusion).", - "gene_id": 1, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 19, - "coordinates": { - "chromosome": "17", - "start": 57697219, - "stop": 57768072, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000269122.3", - "chromosome2": "2", - "start2": 29415640, - "stop2": 29446394, - "representative_transcript2": "ENST00000389048.3", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - } - ], - "type": "variant_group" - } - ], - "assertions": [], - "variant_aliases": [], - "hgvs_expressions": [], - "clinvar_entries": [ - "N/A" - ], - "allele_registry_id": null - }, - "ASSERTIONS": [ - { - "id": 3, - "type": "assertion", - "name": "AID3", - "summary": "Lung adenocarcinoma positive for ALK-FUSIONS have been found to be sensitive to crizotinib treatment", - "description": "ALK-FUSIONS induce an active form of the receptor tyrosine kinase ALK. ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation. the ALK inhibitor crizotinib was effective in lung cancer patients with ALK fusions and was granted accelerated FDA approval in 2011. The Vysis break-apart FISH assay is an FDA approved test for the presence of ALK fusion. NCCN guideline version 9.2017 lists crizotinib as approved first-line NSCLC treatment in the presence of ALK fusions but now lists alectinib as preferred first-line therapy.", - "gene": { - "name": "ALK", - "id": 1 - }, - "variant": { - "name": "ALK FUSIONS", - "id": 499 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID276.json b/analysis/civic/examples/harvester/EID276.json deleted file mode 100644 index 1f466117..00000000 --- a/analysis/civic/examples/harvester/EID276.json +++ /dev/null @@ -1,4048 +0,0 @@ -{ - "EVIDENCE": { - "id": 276, - "name": "EID276", - "description": "Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 4, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 181, - "name": "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.", - "citation": "Paez et al., 2004, Science", - "citation_id": "15118125", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15118125", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2004, - "month": 6, - "day": 4 - }, - "journal": "Science", - "full_journal_title": "Science (New York, N.Y.)", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [], - "assertions": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ], - "gene_id": 19 - }, - "GENE": { - "id": 19, - "name": "EGFR", - "entrez_id": 1956, - "description": "EGFR is widely recognized for its importance in cancer. Amplification and mutations have been shown to be driving events in many cancer types. Its role in non-small cell lung cancer, glioblastoma and basal-like breast cancers has spurred many research and drug development efforts. Tyrosine kinase inhibitors have shown efficacy in EGFR amplfied tumors, most notably gefitinib and erlotinib. Mutations in EGFR have been shown to confer resistance to these drugs, particularly the variant T790M, which has been functionally characterized as a resistance marker for both of these drugs. The later generation TKI's have seen some success in treating these resistant cases, and targeted sequencing of the EGFR locus has become a common practice in treatment of non-small cell lung cancer. \nOverproduction of ligands is another possible mechanism of activation of EGFR. ERBB ligands include EGF, TGF-a, AREG, EPG, BTC, HB-EGF, EPR and NRG1-4 (for detailed information please refer to the respective ligand section).", - "variants": [ - { - "name": "N771_P772insL", - "id": 3304, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Overexpression", - "id": 193, - "evidence_items": { - "accepted_count": 9, - "rejected_count": 2, - "submitted_count": 3 - } - }, - { - "name": "Exon 4 Deletion", - "id": 252, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Exon 20 Insertion", - "id": 726, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "Exon 18 Overexpression", - "id": 375, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Expression", - "id": 354, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "Wildtype", - "id": 2174, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "L747_T751delinsP", - "id": 1010, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "D770_N771insGL", - "id": 1514, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Amplification", - "id": 190, - "evidence_items": { - "accepted_count": 11, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "A750T", - "id": 2332, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Copy Number Variation", - "id": 191, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Exon 19 Deletion", - "id": 133, - "evidence_items": { - "accepted_count": 16, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "G465E", - "id": 2603, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F404V", - "id": 2617, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F404I", - "id": 2616, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E884K", - "id": 1390, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709Q", - "id": 1413, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D761N", - "id": 1013, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "Mutation", - "id": 442, - "evidence_items": { - "accepted_count": 16, - "rejected_count": 1, - "submitted_count": 3 - } - }, - { - "name": "L858R", - "id": 33, - "evidence_items": { - "accepted_count": 36, - "rejected_count": 1, - "submitted_count": 4 - } - }, - { - "name": "T790M", - "id": 34, - "evidence_items": { - "accepted_count": 30, - "rejected_count": 2, - "submitted_count": 9 - } - }, - { - "name": "Y1092 PHOSPHORYLATION", - "id": 390, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EGFR-RAD51", - "id": 2203, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "R451C", - "id": 454, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "I462R", - "id": 2600, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S464L", - "id": 2601, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S492R", - "id": 453, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I462K", - "id": 2599, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S464T", - "id": 2602, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G465V", - "id": 2604, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K467N", - "id": 2605, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K489Q", - "id": 2606, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719S", - "id": 134, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "K489E", - "id": 2607, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I491K", - "id": 2608, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I491R", - "id": 2609, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S492C", - "id": 2610, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441G", - "id": 2611, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441D", - "id": 2612, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V441F", - "id": 2613, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S442R", - "id": 2614, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S442I", - "id": 2615, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T415M", - "id": 2618, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "M766_A767insASV", - "id": 2213, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "delL747_P753insS", - "id": 2215, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D770delinsGY", - "id": 2214, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P772_H773insH", - "id": 2217, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "3' UTR MUTATION", - "id": 253, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "AUTOCRINE ACTIVATION", - "id": 309, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 2, - "submitted_count": 0 - } - }, - { - "name": "C797S", - "id": 415, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "S768N", - "id": 1443, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "Gain-of-function", - "id": 1765, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G465R", - "id": 443, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719", - "id": 718, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S720", - "id": 720, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S752_I759delSPKANKEI", - "id": 891, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L838V", - "id": 1018, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "R108K", - "id": 994, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861Q", - "id": 1020, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "T263P", - "id": 995, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V742A", - "id": 1001, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "E746_T751>I", - "id": 1003, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "E746V", - "id": 1005, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 6 - } - }, - { - "name": "L747_T751>Q", - "id": 1008, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "E746_S752>D", - "id": 1009, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_T751delLREAT", - "id": 1007, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_P753>Q", - "id": 1011, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "G810S", - "id": 1016, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "R776C", - "id": 1181, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S784F", - "id": 1182, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "N826S", - "id": 1188, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G719D", - "id": 1420, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_S752>A", - "id": 1433, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "H773_V774insH", - "id": 1446, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L747_S752del", - "id": 890, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 7 - } - }, - { - "name": "L747_A750>P", - "id": 1006, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "D770_N771insSVD", - "id": 1445, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "L838P", - "id": 1457, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T847I", - "id": 1463, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861R", - "id": 1477, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E868G", - "id": 1482, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D770_N771insNPG", - "id": 1569, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V774_C775insHV", - "id": 1567, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "W731L", - "id": 1571, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T785A", - "id": 1573, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E734Q", - "id": 1572, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y801H", - "id": 1575, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E709_T710>D", - "id": 1577, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "V769A", - "id": 1578, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "N771>GY", - "id": 1581, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P546S", - "id": 1582, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T854A", - "id": 1467, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P848L", - "id": 1465, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E746_A750>IP", - "id": 1635, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K745_E749delKELRE", - "id": 1638, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "M766_A767insAI", - "id": 1664, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y764_V765insHH", - "id": 1665, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P772_V774insPHV", - "id": 1668, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "P772_H773insYNP", - "id": 1667, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Y69FS*11", - "id": 1672, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "N771DELinsVH", - "id": 1662, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V851I", - "id": 1466, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L747_S752delinsQ", - "id": 1580, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Ex19 del L858R", - "id": 1854, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L861", - "id": 1866, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V774A", - "id": 1892, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L747P", - "id": 1891, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V774M", - "id": 1894, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V834I", - "id": 1897, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "N842S", - "id": 1899, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "N826Y", - "id": 1896, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "A702S", - "id": 2255, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709K and G719A", - "id": 2256, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Exon 18 deletion", - "id": 2257, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E709A and G719C", - "id": 2258, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "I744_K745insKIPVAI", - "id": 2259, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "S768_D770dup", - "id": 1511, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G598V", - "id": 997, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "L747_P753delinsS", - "id": 1012, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 8 - } - }, - { - "name": "R705K", - "id": 2333, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "RARE EGRF MUT", - "id": 2334, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "RARE Exon 18-21 Mutation", - "id": 1863, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_T751delinsVA", - "id": 1214, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "E746_A750del", - "id": 1002, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 19 - } - }, - { - "name": "K467T", - "id": 455, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P753S", - "id": 460, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G724S", - "id": 317, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "S768I", - "id": 562, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "E746G", - "id": 724, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L718V and L718Q", - "id": 2997, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "L718Q", - "id": 2999, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "V769_770insASV", - "id": 736, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "D761Y", - "id": 712, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "T725M", - "id": 861, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L718V", - "id": 3000, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "A289V", - "id": 996, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "E746_T751delinsA", - "id": 1004, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 5 - } - }, - { - "name": "R831H", - "id": 1017, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "G719A", - "id": 999, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "A763_Y764insFQEA", - "id": 1515, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "A859T", - "id": 1474, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "A864T", - "id": 1187, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "H773_V774insNPH", - "id": 1513, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "C797Y", - "id": 1574, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "A767_V769dupASV", - "id": 1579, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "K806E", - "id": 1895, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D770_N771insGT", - "id": 1566, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K757R", - "id": 723, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "C797G", - "id": 3003, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L792H", - "id": 3004, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G719X", - "id": 2912, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R832L", - "id": 2741, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "M766Q", - "id": 2745, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "VIII", - "id": 312, - "evidence_items": { - "accepted_count": 7, - "rejected_count": 0, - "submitted_count": 2 - } - } - ], - "aliases": [ - "ERRP", - "EGFR", - "mENA", - "PIG61", - "NISBD2", - "HER1", - "ERBB1", - "ERBB" - ], - "type": "gene" - }, - "VARIANT": { - "id": 33, - "entrez_name": "EGFR", - "entrez_id": 1956, - "name": "L858R", - "description": "EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies.", - "gene_id": 19, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 375, - "coordinates": { - "chromosome": "7", - "start": 55259515, - "stop": 55259515, - "reference_bases": "T", - "variant_bases": "G", - "representative_transcript": "ENST00000275493.2", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 229, - "name": "EID229", - "description": "There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 162, - "name": "Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21.", - "citation": "Lim et al., 2014, J Thorac Oncol", - "citation_id": "24736073", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24736073", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 4 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 276, - "name": "EID276", - "description": "Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 4, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 181, - "name": "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.", - "citation": "Paez et al., 2004, Science", - "citation_id": "15118125", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15118125", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2004, - "month": 6, - "day": 4 - }, - "journal": "Science", - "full_journal_title": "Science (New York, N.Y.)", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 879, - "name": "EID879", - "description": "A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001).", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 592, - "name": "Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.", - "citation": "Sequist et al., 2013, J. Clin. Oncol.", - "citation_id": "23816960", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23816960", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 9, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00949650", - "name": "BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation", - "description": "This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00949650" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 883, - "name": "EID883", - "description": "In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 594, - "name": "Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.", - "citation": "Yang et al., 2012, Lancet Oncol.", - "citation_id": "22452895", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22452895", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 5 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00525148", - "name": "LUX Lung 2 Phase II Single Arm BIBW 2992 \"Afatinib\" in NSCLC With EGFR Activating Mutations", - "description": "The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by RECIST criteria in patients with advanced NSCLC Stage IIIB or IV whose tumors harbor activating mutations within exon 18 to exon 21 of the EGFR receptor. Patients progressing or relapsing after one prior cytotoxic chemotherapy regimen as well as chemotherapy na\u00efve patients (only in stage 2) will be allowed to enter into the trial.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00525148" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 885, - "name": "EID885", - "description": "A randomized phase 3 trial (NCT00446225) involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 595, - "name": "Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.", - "citation": "Rosell et al., 2012, Lancet Oncol.", - "citation_id": "22285168", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22285168", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 3 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00446225", - "name": "Phase III Study (Tarceva\u00ae) vs Chemotherapy to Treat Advanced Non-Small Cell Lung Cancer (NSCLC) in Patients With Mutations in the TK Domain of EGFR", - "description": "A Phase III, multicenter, open-label, randomized trial of Erlotinib (Tarceva\u00ae) versus chemotherapy in patients with advanced NSCLC with mutations in the Tyrosine Kinase (TK) domain of the EGFR.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00446225" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 968, - "name": "EID968", - "description": "Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 669, - "name": "In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.", - "citation": "Hirano et al., 2015, Oncotarget", - "citation_id": "26515464", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26515464", - "open_access": true, - "pmc_id": "PMC4770737", - "publication_date": { - "year": 2015, - "month": 11, - "day": 17 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 982, - "name": "EID982", - "description": "Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 679, - "name": "Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.", - "citation": "Wu et al., 2014, Lancet Oncol.", - "citation_id": "24439929", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24439929", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 2 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01121393", - "name": "BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)", - "description": "To investigate the efficacy and safety of BIBW 2992 compared to standard first-line chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01121393" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 275, - "name": "EID275", - "description": "In NSCLC patients treated with EGFR tyrosine kinase inhibitors, the presence of L858R mutation is prognostic for better progression free survival.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 182, - "name": "Clinical predictors of response to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.", - "citation": "Fukihara et al., 2014, Oncology", - "citation_id": "24457318", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24457318", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014 - }, - "journal": "Oncology", - "full_journal_title": "Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 1665, - "name": "EID1665", - "description": "90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and the L858R EGFR mutation was associated with longer time to treatment failure than those with wild-type EGFR (median 9.1 versus 2.1). In multivariate analysis, L858R mutations plus adenocarcinoma was a significant predictive factor for time to treatment failure (HR = 0.1030; P = .0004).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1127, - "name": "Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy.", - "citation": "Yang et al., 2008, J. Clin. Oncol.", - "citation_id": "18509184", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18509184", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 6, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2621, - "name": "EID2621", - "description": "In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1501, - "name": "Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial.", - "citation": "Douillard et al., 2010, J. Clin. Oncol.", - "citation_id": "20038723", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20038723", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 2, - "day": 10 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00076388", - "name": "Iressa Versus Docetaxel (Taxotere)", - "description": "The purpose of this study is to compare the effects of ZD1839 or docetaxel in patients with advanced non-small cell lung cancer (NSCLC) that has recurred or progressed after receiving prior treatment with platinum-based chemotherapy.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00076388" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2623, - "name": "EID2623", - "description": "In a phase 3 clinical trial of Japanese NSCLC patients with EGFR mutations (n=230), patients treated with gefitinib were associated with improved progression free survival (10.8 months vs 5.4 months, HR: 0.30, 95% CI: 0.22-0.41, P<0.001), compared to patients treated with carboplatin and paclitaxel combination therapy. The frequency of mutation of exon 19 deletion and L858R was 25.2% (58/230) and 21.3% (49/230), respectively.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1508, - "name": "Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.", - "citation": "Maemondo et al., 2010, N. Engl. J. Med.", - "citation_id": "20573926", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20573926", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2010, - "month": 6, - "day": 24 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2624, - "name": "EID2624", - "description": "Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was L858R. The patient was a female former smoker who had lung adenocarcinoma histology, and demonstrated response for 5 months, with overall survival 8 months.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 1, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1509, - "name": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib.", - "citation": "Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A.", - "citation_id": "15329413", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15329413", - "open_access": true, - "pmc_id": "PMC516528", - "publication_date": { - "year": 2004, - "month": 9, - "day": 7 - }, - "journal": "Proc. Natl. Acad. Sci. U.S.A.", - "full_journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2626, - "name": "EID2626", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to lapatinib (IC50: 63nM vs. 534nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 45, - "name": "Lapatinib", - "ncit_id": "C26653", - "aliases": [ - "GW572016", - "GW2016", - "GW 2016", - "GSK572016" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2628, - "name": "EID2628", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated sensitivity to neratinib (IC50: 0.0049 \u03bcmol/L) compared to EGFRwt A549 cells (IC50 > 1 \u03bcmol/L).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 52, - "name": "Neratinib", - "ncit_id": "C49094", - "aliases": [ - "PB-272", - "PB 272", - "HKI-272", - "HKI 272", - "2-Butenamide, N-(4-((3-chloro-4-(2-pyridinylmethoxy)phenyl)amino)-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-, (2E)-", - "(2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1526, - "name": "Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272.", - "citation": "Shimamura et al., 2006, Cancer Res.", - "citation_id": "16818618", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/16818618", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2006, - "month": 7, - "day": 1 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2629, - "name": "EID2629", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to afatinib (IC50: 0.7nM vs. 60nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2630, - "name": "EID2630", - "description": "In a phase 2b/3 study of 585 stage IIIB-IV lung adenocarcinoma patients who had a previous round of EGFR-TKI treatment, archival material was available for 141 patients. EGFR mutational analysis revealed that 96 tumors had an EGFR mutation, of which 76 (79%) were positive for either L858R or a deletion in exon 19. These mutations were associated with improved progression-free survival (median 3.3 months vs 1.0 month ; HR:0.51, 95% CI:0.31-0.85, P<0.009) compared to placebo control.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": null, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 1510, - "name": "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.", - "citation": "Miller et al., 2012, Lancet Oncol.", - "citation_id": "22452896", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22452896", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 5 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00656136", - "name": "BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)", - "description": "This randomized, double-blind, multi-center Phase IIb/III trial will be performed in patients with NSCLC who have received previous treatment with at least one but not more than two lines of cytotoxic chemotherapy (one line must have been a platinum-containing regimen) and either gefitinib or erlotinib for a period of at least 12 weeks and then progressed. The primary objective of this randomized trial is to determine the efficacy of BIBW 2992 as a single agent (Arm A) as compared to a matching placebo (Arm B) in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00656136" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2631, - "name": "EID2631", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to canertinib (IC50: 1nM vs. 198nM) compared to wildtype EGFR cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 465, - "name": "Canertinib", - "ncit_id": "C77588", - "aliases": [ - "N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide", - "2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2633, - "name": "EID2633", - "description": "EGFR L858R mutation has been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib.In an in vitro study using PC9 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. PC9 cells demonstrated an increased sensitivity to gefitinib (IC50: 11.0-12.0 nmol/L vs 61.0 nmol/L) compared to NCI-H2073 cells (EGFR wild type).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 427, - "name": "Durvalumab", - "ncit_id": "C103194", - "aliases": [ - "MEDI4736", - "MEDI-4736", - "Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide With Human Monoclonal MEDI4736 Kappa-chain, Dimer", - "Imfinzi" - ] - } - ], - "rating": 1, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "rejected", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2634, - "name": "EID2634", - "description": "In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1513, - "name": "First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.", - "citation": "Han et al., 2012, J. Clin. Oncol.", - "citation_id": "22370314", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22370314", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 4, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4265, - "name": "EID4265", - "description": "MCF-7 cells were transduced with YFP tagged EGFR with E746_A750delELREA mutation, or YFP EGFR wildtype, and stained for ectopic YFP EGFR and phospho-Akt as a readout for EGFR pathway activity. Increased p-Akt stain was seen with ectopic mutant EGFR over wildtype cells. Parallel erlotinib incubations of cells with wildtype EGFR induced recompartmentalization of ectopic EGFR protien only at high concentration (10uM). Addition of erlotinib to mutant EGFR cell incubations reduced p-Akt signal and induced recompartmentalization of ectopic EGFR protien at considerably lower conecntration (100 nM) erlotinib. These results indicate the EGFR L858R variant as a growth pathway driver targetable by erlotinib.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1991, - "name": "Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.", - "citation": "de Gunst et al., 2007, Mol. Cancer", - "citation_id": "17877814", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17877814", - "open_access": true, - "pmc_id": "PMC2064929", - "publication_date": { - "year": 2007, - "month": 9, - "day": 18 - }, - "journal": "Mol. Cancer", - "full_journal_title": "Molecular cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4284, - "name": "EID4284", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to erlotinib (IC50: 40nM vs. 110nM) compared to EGFR wild type cells.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1525, - "name": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "citation": "Li et al., 2008, Oncogene", - "citation_id": "18408761", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18408761", - "open_access": true, - "pmc_id": "PMC2748240", - "publication_date": { - "year": 2008, - "month": 8, - "day": 7 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4285, - "name": "EID4285", - "description": "In an in vitro study, a MCF-7 cell line expressing EGFR L858R mutation demonstrated sensitivity to erlotinib treatment, compared to MCF-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing YFP signal-EGFR relocation.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1993, - "name": "Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry.", - "citation": "Harada et al., 2011, Oncogene", - "citation_id": "21132006", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21132006", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 4, - "day": 14 - }, - "journal": "Oncogene", - "full_journal_title": "Oncogene", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4286, - "name": "EID4286", - "description": "In an in vitro study, Ba/F3 and NCI-H3255 cell lines expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment (IC50=0.006 and 0.068 \u00b5M). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1230, - "name": "Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.", - "citation": "Yasuda et al., 2013, Sci Transl Med", - "citation_id": "24353160", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24353160", - "open_access": true, - "pmc_id": "PMC3954775", - "publication_date": { - "year": 2013, - "month": 12, - "day": 18 - }, - "journal": "Sci Transl Med", - "full_journal_title": "Science translational medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4287, - "name": "EID4287", - "description": "In an in vitro study, CHO and NCI-H3255 cells expressing EGFR L858R mutation were associated with sensitivity to erlotinib treatment. Sensitivity was determined by assessing cell density.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": null, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2070, - "name": "Differential protein stability of EGFR mutants determines responsiveness to tyrosine kinase inhibitors.", - "citation": "Ray et al., 2016, Oncotarget", - "citation_id": "27612423", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27612423", - "open_access": true, - "pmc_id": "PMC5356576", - "publication_date": { - "year": 2016, - "month": 10, - "day": 18 - }, - "journal": "Oncotarget", - "full_journal_title": "Oncotarget", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4288, - "name": "EID4288", - "description": "This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One patient was biopsied twice following crizotinib progression and once pre-treatment. This patient was a 27 year old female with one pack year who experienced partial response on crizotinib as 4th line therapy. The patient's pre-crizotinib biopsy was ALK+ and lacked the EGFR mutation. A biopsy taken after 63 days on crizotinib showed EGFR L858R mutation and lacked ALK gene rearrangement by FISH (ALK Loss). Of note, a second post-treatment biopsy (after 113 on crizotinib) showed ALK rearrangement but lacked EGFR mutation. The authors interpreted the emergence of an ALK negative tumor (first post-critozitinib biopsy) as evidence of a separate oncogenic driver (EGFR L858R).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 12, - "name": "Crizotinib", - "ncit_id": "C74061", - "aliases": [ - "Xalkori", - "PF-2341066", - "PF-02341066", - "MET Tyrosine Kinase Inhibitor PF-02341066", - "2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-", - "(R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine" - ] - } - ], - "rating": 3, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 507, - "name": "Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.", - "citation": "Doebele et al., 2012, Clin. Cancer Res.", - "citation_id": "22235099", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22235099", - "open_access": true, - "pmc_id": "PMC3311875", - "publication_date": { - "year": 2012, - "month": 3, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4290, - "name": "EID4290", - "description": "In a prospective study of 46 Caucasian, advanced lung adenocarcinoma patients harboring EGFR mutations, first-line erlotinib treatment was assessed. Average PFS and OS for these 46 patients was 11 months (95% CI: 9.7-12.3 months) and 23 months (95% CI: 21.3-28.6+ months), respectively. A PFS rate of 81% at three months met the primary endpoint of presumed superiority over chemotherapy. Clinical benefit (CR+PR+SD) rate was 81%. Fifteen patients harbored EGFR L858R mutations, which was the only mutation found in exon 21. The authors note similar response profiles for exon 19 (27/46) and exon 21 mutations (15/46) to the overall population.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2067, - "name": "Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT).", - "citation": "De Gr\u00e8ve et al., 2016, PLoS ONE", - "citation_id": "27032107", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27032107", - "open_access": true, - "pmc_id": "PMC4816447", - "publication_date": { - "year": 2016 - }, - "journal": "PLoS ONE", - "full_journal_title": "PloS one", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00339586", - "name": "First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene", - "description": "Current chemotherapy for advanced non-small cell lung cancer, not amenable for curative local treatment (surgery or chemoradiotherapy), has a modest life-prolonging effect and can improve quality of life. There is however no potential for long-term cure for these patients. Chemotherapy also produces variable and often significant toxicity. Current retrospective evidence suggests that significant clinical responses can be obtained when patients whose cancer cells have an EGFR TKD mutation are treated with an EGFR TKI. The ease of administration and toxicity profile of TKI compare favourably with that of chemotherapy, even single agents such as for example gemcitabine The present study will establish the clinical benefit rate of TKI as a first line treatment in patients with EGFR mutations and thus estimate the proportion of patients who might benefit for a prolonged period from a treatment with a modest toxicity profile.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00339586" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4291, - "name": "EID4291", - "description": "In an in vitro study, Ba/F3 cell line expressing EGFR L858R was associated with sensitivity to erlotinib treatment (IC50 26.9 \u00b1 12.4). Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation, and EGFR auto-phosphorylation.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2086, - "name": "EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.", - "citation": "Konduri et al., 2016, Cancer Discov", - "citation_id": "27102076", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27102076", - "open_access": true, - "pmc_id": "PMC4893907", - "publication_date": { - "year": 2016 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4292, - "name": "EID4292", - "description": "In an in vitro study, Ba/F3 cell line expressing EGFR L858R did not show sensitivity to cetuximab treatment, while cells expressing EGFR-RAD51 fusion were sensitive. Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation and EGFR auto-phosphorylation.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2086, - "name": "EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.", - "citation": "Konduri et al., 2016, Cancer Discov", - "citation_id": "27102076", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27102076", - "open_access": true, - "pmc_id": "PMC4893907", - "publication_date": { - "year": 2016 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4293, - "name": "EID4293", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to erlotinib (IC50: 8 and 11 nM) compared to EGFRwt NCI-H2073 cells (IC50: 108 nM; 95%CI 52-223 nM).", - "disease": { - "id": 174, - "name": "Lung Small Cell Carcinoma", - "display_name": "Lung Small Cell Carcinoma", - "doid": "5409", - "url": "http://www.disease-ontology.org/?id=DOID:5409" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4295, - "name": "EID4295", - "description": "In an in vitro study, a Ba/F3 cell line expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0\u201310 uM).", - "disease": { - "id": 695, - "name": "High Grade Glioma", - "display_name": "High Grade Glioma", - "doid": "3070", - "url": "http://www.disease-ontology.org/?id=DOID:3070" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1608, - "name": "Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.", - "citation": "Lee et al., 2006, PLoS Med.", - "citation_id": "17177598", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/17177598", - "open_access": true, - "pmc_id": "PMC1702556", - "publication_date": { - "year": 2006, - "month": 12 - }, - "journal": "PLoS Med.", - "full_journal_title": "PLoS medicine", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2994, - "name": "EID2994", - "description": "On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1724, - "name": "U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations.", - "citation": "Khozin et al., 2014, Oncologist", - "citation_id": "24868098", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24868098", - "open_access": true, - "pmc_id": "PMC4077454", - "publication_date": { - "year": 2014, - "month": 7 - }, - "journal": "Oncologist", - "full_journal_title": "The oncologist", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2997, - "name": "EID2997", - "description": "Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1725, - "name": "Afatinib: first global approval.", - "citation": "Dungo et al., 2013, Drugs", - "citation_id": "23982599", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23982599", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 9 - }, - "journal": "Drugs", - "full_journal_title": "Drugs", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4860, - "name": "EID4860", - "description": "The authors pooled patients with exon 19 deletion and L858R EGFR (Exon 21) mutations from both studies (The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)) to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. For those (exon19/21), the median PFS was 14.6 months with dacomitinib and 9.6 months with erlotinib The median survival was 26.6 months with dacomitinib versus 23.2 months with erlotinib.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 44, - "name": "Dacomitinib", - "ncit_id": "C53398", - "aliases": [ - "Vizimpro", - "PF-299804", - "PF-00299804-03", - "PF-00299804", - "EGFR Inhibitor PF-00299804", - "(2E)-N-(4-((3-Chloro-4-Fluorophenyl)Amino)-7-Methoxyquinazolin-6-yl)-4-Piperidin-1-ylbut-2-Enamide" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2158, - "name": "Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.", - "citation": "Ramalingam et al., 2016, Ann. Oncol.", - "citation_id": "26768165", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26768165", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 3 - }, - "journal": "Ann. Oncol.", - "full_journal_title": "Annals of oncology : official journal of the European Society for Medical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01360554", - "name": "ARCHER 1009 : A Study Of Dacomitinib (PF-00299804) Vs. Erlotinib In The Treatment Of Advanced Non-Small Cell Lung Cancer", - "description": "This is a multinational, multicenter, randomized,double-blinded, Phase 3 study comparing the efficacy and safety of treatment with PF-00299804 to treatment with erlotinib in patients with advanced non-small cell lung cancer, previously treated with at least one prior regimen. Analyses of primary objective (Progression Free Survival) will be done in two co-primary populations as defined in the protocol.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01360554" - }, - { - "nct_id": "NCT00769067", - "name": "A Randomized Trial Of PF-00299804 Taken Orally Versus Erlotinib Taken Orally For Treatment Of Advanced Non-Small Cell Lung Cancer That Has Progressed After One Or Two Prior Chemotherapy Regimen", - "description": "This study will compare PF-00299804 given orally on continuous schedule to the approved drug, erlotinib, in patients whose non-small cell lung cancer has progressed after chemotherapy; patients will be randomized to receive one of these drugs, and followed for efficacy and tolerance of each.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00769067" - } - ] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2632, - "name": "EID2632", - "description": "In a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma), EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib. Two patients had the del L858R mutation. One patient was a male former smoker who demonstrated response for 3 months with overall survival of 3.5 months, and the other patient was a female never smoker who had response for 6 months and overall survival of 17+ months as the patient was alive at study end.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1509, - "name": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib.", - "citation": "Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A.", - "citation_id": "15329413", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/15329413", - "open_access": true, - "pmc_id": "PMC516528", - "publication_date": { - "year": 2004, - "month": 9, - "day": 7 - }, - "journal": "Proc. Natl. Acad. Sci. U.S.A.", - "full_journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 3811, - "name": "EID3811", - "description": "EGFR L858R was expressed in Ba/F3 cells which do not contain endogenous EGFR, and conferred growth factor independance to the cells. Cells were plated and treated with 1st generation EGFR inhibitors Gefitinib, Erlotinib, or the the tool compound AEE788, and IC50 values were measured. L858R EGFR cells had very low IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib=12, Erlotinib=6, AEE788=6), indicating sensitivity to all three constructs.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - }, - { - "id": 90, - "name": "Multikinase Inhibitor AEE788", - "ncit_id": "C48369", - "aliases": [ - "AEE788", - "AEE-788", - "AEE 788" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1528, - "name": "Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy.", - "citation": "Kancha et al., 2009, Clin. Cancer Res.", - "citation_id": "19147750", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/19147750", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2009, - "month": 1, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 5922, - "name": "EID5922", - "description": "In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR L858R demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR \n expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation.", - "disease": { - "id": 216, - "name": "Cancer", - "display_name": "Cancer", - "doid": "162", - "url": "http://www.disease-ontology.org/?id=DOID:162" - }, - "drugs": [ - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 2081, - "name": "Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma.", - "citation": "Foster et al., 2010, World J Surg Oncol", - "citation_id": "20942962", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20942962", - "open_access": true, - "pmc_id": "PMC2970593", - "publication_date": { - "year": 2010, - "month": 10, - "day": 13 - }, - "journal": "World J Surg Oncol", - "full_journal_title": "World journal of surgical oncology", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 6183, - "name": "EID6183", - "description": "In a Japanese Phase III clinical trial, noninferiority of Gefitinib as compared to Erlotinib was assessed in 561 postoperative recurrent or stage IIIb/VI patients who had undergone prior chemotherapy treatment but no tyrosine kinase inhibitor therapy. In a subset of patients with sole EGFR L858R, there was an insignificant difference between the objective response and disease control rates for patients treated with erlotinib (N=67) and gefitinib (N=78). Progression free survival was also not significantly different and did not meet the noninferiority endpoint with Gefitinib and Erlotinib arms at 8.1 and 8.5 months, respectively (HR, 0.938; 95% CI, 0.675 to 1.304; P = .704).", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 2478, - "name": "Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L.", - "citation": "Urata et al., 2016, J. Clin. Oncol.", - "citation_id": "27022112", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27022112", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "day": 20 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 2627, - "name": "EID2627", - "description": "In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to Dacomitinib (IC50: 0.007umol/L vs. >10umol/L) compared to wildtype EGFR cells or compared to reversible TKI drug gefitinib (IC50: 0.075umol/L vs. wild-type >10umol/L).", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 44, - "name": "Dacomitinib", - "ncit_id": "C53398", - "aliases": [ - "Vizimpro", - "PF-299804", - "PF-00299804-03", - "PF-00299804", - "EGFR Inhibitor PF-00299804", - "(2E)-N-(4-((3-Chloro-4-Fluorophenyl)Amino)-7-Methoxyquinazolin-6-yl)-4-Piperidin-1-ylbut-2-Enamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1515, - "name": "PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.", - "citation": "Engelman et al., 2007, Cancer Res.", - "citation_id": "18089823", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18089823", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2007, - "month": 12, - "day": 15 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 8053, - "name": "EID8053", - "description": "A 62 year old patient with 4 pack-year smoking history with back and flank pain was found to have metastatic lung adenocarcinoma by CT and MRI. Targeted NGS sequencing discovered an EGFR L858R mutation and the patient started 80mg osimertinib treatment with excellent response of all disease sites, including brain metastases. The patient had continued response until 8.5 months after treatment initiation when a new liver lesion was found. NGS sequencing of a repeat biopsy detected the original EGFR L858R mutation as well as L718V and L718Q mutations. Afatinib treatment led to a partial response for 4.5 months, at which time disease progression occurred. Biopsy of a progressing liver lesion showed acquired EGFR T790M mutation as well as increase and decrease of L718V and L718Q mutation frequencies, respectively.", - "disease": { - "id": 30, - "name": "Lung Adenocarcinoma", - "display_name": "Lung Adenocarcinoma", - "doid": "3910", - "url": "http://www.disease-ontology.org/?id=DOID:3910" - }, - "drugs": [ - { - "id": 187, - "name": "Osimertinib", - "ncit_id": "C116377", - "aliases": [ - "Tagrisso", - "Mereletinib", - "AZD9291", - "AZD-9291", - "2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3253, - "name": "Drug sensitivity and allele-specificity of first-line osimertinib resistance EGFR mutations.", - "citation": "Starrett et al., 2020, Cancer Res.", - "citation_id": "32193290", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/32193290", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2020, - "month": 3, - "day": 19 - }, - "journal": "Cancer Res.", - "full_journal_title": "Cancer research", - "status": "submitted", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 4294, - "name": "EID4294", - "description": "In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to AZD9291 (IC50: 60 and 49 nM) compared to EGFRwt NCI-H2073 cells (IC50: 1865 nM; 95%CI 872-3988 nM). In vivo experiments with NCI-H3255 xenograft models showed drastic tumour volume reduction upon treatment with 5mg/kg/day AZD9291.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 187, - "name": "Osimertinib", - "ncit_id": "C116377", - "aliases": [ - "Tagrisso", - "Mereletinib", - "AZD9291", - "AZD-9291", - "2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 665, - "name": "AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.", - "citation": "Cross et al., 2014, Cancer Discov", - "citation_id": "24893891", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24893891", - "open_access": true, - "pmc_id": "PMC4315625", - "publication_date": { - "year": 2014, - "month": 9 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "partially curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - }, - { - "id": 347, - "name": "EID347", - "description": "Median survival of patients with EGFR L858R mutation is better than those with wild type EGFR.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Better Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 213, - "name": "Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer.", - "citation": "Douillard et al., 2014, J Thorac Oncol", - "citation_id": "24662454", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24662454", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 5 - }, - "journal": "J Thorac Oncol", - "full_journal_title": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 33, - "phenotypes": [] - } - ], - "variant_groups": [], - "assertions": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 6, - "type": "assertion", - "name": "AID6", - "summary": "EGFR L858R positive NSCLC is sensitive to afatinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis, including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor afatinib is FDA approved, and is recommended (category 1) by NCCN guidelines along with erlotinib, gefitinib and osimertinib as first line systemic therapy in NSCLC with sensitizing EGFR mutation.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 146, - "name": "Afatinib", - "ncit_id": "C66940", - "aliases": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ], - "variant_aliases": [ - "LEU858ARG", - "RS121434568" - ], - "hgvs_expressions": [ - "NC_000007.13:g.55259515T>G", - "NM_005228.4:c.2573T>G", - "ENST00000275493.2:c.2573T>G", - "NP_005219.2:p.Leu858Arg" - ], - "clinvar_entries": [ - "376280", - "16609", - "376282" - ], - "allele_registry_id": "CA126713" - }, - "ASSERTIONS": [ - { - "id": 5, - "type": "assertion", - "name": "AID5", - "summary": "Non-small cell lung cancer with EGFR L858R mutation is sensitive to erlotininb or gefitinib.", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitors erlotinib and gefitinib are associated with improved progression free survival over chemotherapy in EGFR L858R patients. NCCN guidelines recommend (category 1) erlotinib and gefitinib for NSCLC with sensitizing EGFR mutations, along with afatinib and osimertinib.", - "gene": { - "name": "EGFR", - "id": 19 - }, - "variant": { - "name": "L858R", - "id": 33 - }, - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID405.json b/analysis/civic/examples/harvester/EID405.json deleted file mode 100644 index ad6a3166..00000000 --- a/analysis/civic/examples/harvester/EID405.json +++ /dev/null @@ -1,380 +0,0 @@ -{ - "EVIDENCE": { - "id": 405, - "name": "EID405", - "description": "A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA resulting from a ~400kb deletion was observed in 100% (15/15) fibrolamellar hepatocellular carcinomas examined. The fusion was confirmed at both RNA and DNA level in all primary and metastatic tumor samples but not in adjacent normal tissue. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity.", - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 22, - "name": "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.", - "citation": "Honeyman et al., 2014, Science", - "citation_id": "24578576", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24578576", - "open_access": true, - "pmc_id": "PMC4286414", - "publication_date": { - "year": 2014, - "month": 2, - "day": 28 - }, - "journal": "Science", - "full_journal_title": "Science (New York, N.Y.)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 31, - "phenotypes": [], - "assertions": [ - { - "id": 24, - "type": "assertion", - "name": "AID24", - "summary": "DNAJB1-PRKACA fusion is highly sensitive and specific for diagnosis of fibrolamellar hepatocellular carcinoma", - "description": "A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA, resulting from a ~400kb genomic deletion, has been reported has highly recurrent in fibrolamellar HCC. Detection of this fusion by RNAseq, RT-PCR and FISH has subsequently shown this fusion to be highly sensitive and specific for diagnosis of fibrolamellar HCC and mixed fibrolamellar HCC. Several hundred fibrolamellar HCC, non-FL HCC or non-malignant tissues have now been assayed to demonstrate this.", - "gene": { - "name": "PRKACA", - "id": 17 - }, - "variant": { - "name": "DNAJB1-PRKACA", - "id": 31 - }, - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "evidence_type": "Diagnostic", - "evidence_direction": "Supports", - "clinical_significance": "Positive", - "fda_regulatory_approval": false, - "status": "accepted" - } - ], - "gene_id": 17 - }, - "GENE": { - "id": 17, - "name": "PRKACA", - "entrez_id": 5566, - "description": "PRKACA has been studied in breast cancer and has been found to mediate resistance to HER2 targeted therapies. It has also been found to contain a mutation hotspot that contributes to neoplastic behavior in neuroendocrine cancers. In hepatocellular fibrolamellar carcinoma (FL-HCC), the fusion DNAJB1 to PRKACA is suggested to be a diagnostic marker for this rare subtype of HCC. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity.", - "variants": [ - { - "name": "DNAJB1-PRKACA", - "id": 31, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 0 - } - } - ], - "aliases": [ - "CAFD1", - "PRKACA", - "PPNAD4", - "PKACA" - ], - "type": "gene" - }, - "VARIANT": { - "id": 31, - "entrez_name": "PRKACA", - "entrez_id": 5566, - "name": "DNAJB1-PRKACA", - "description": "This fusion has been found to be very recurrent in the rare form of adolescent liver cancer, fibrolamellar hepatocellular carcinoma. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity. The presence of this fusion may be used as a diagnostic marker for this rare tumor type.", - "gene_id": 17, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 75, - "coordinates": { - "chromosome": "19", - "start": 14628951, - "stop": 14629232, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000254322.2", - "chromosome2": "19", - "start2": 14202500, - "stop2": 14218221, - "representative_transcript2": "ENST00000308677.4", - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 754, - "name": "EID754", - "description": "The DNAJB1-PRKACA fusion was detected in 79% (58/73) of fibrolamellar hepatocellular carcinomas assayed.", - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 499, - "name": "Unique genomic profile of fibrolamellar hepatocellular carcinoma.", - "citation": "Cornella et al., 2015, Gastroenterology", - "citation_id": "25557953", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25557953", - "open_access": true, - "pmc_id": "PMC4521774", - "publication_date": { - "year": 2015, - "month": 4 - }, - "journal": "Gastroenterology", - "full_journal_title": "Gastroenterology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 31, - "phenotypes": [] - }, - { - "id": 405, - "name": "EID405", - "description": "A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA resulting from a ~400kb deletion was observed in 100% (15/15) fibrolamellar hepatocellular carcinomas examined. The fusion was confirmed at both RNA and DNA level in all primary and metastatic tumor samples but not in adjacent normal tissue. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity.", - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 22, - "name": "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.", - "citation": "Honeyman et al., 2014, Science", - "citation_id": "24578576", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24578576", - "open_access": true, - "pmc_id": "PMC4286414", - "publication_date": { - "year": 2014, - "month": 2, - "day": 28 - }, - "journal": "Science", - "full_journal_title": "Science (New York, N.Y.)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 31, - "phenotypes": [] - }, - { - "id": 532, - "name": "EID532", - "description": "RT-PCR and FISH assays were developed for the detection of rearrangements of the PRKACA locus. A total of 106 primary liver tumors were studied by RT-PCR (26 fibrolamellar carcinomas, 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas). FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas. Evidence of the DNAJB1-PRKACA fusion was found in all fibrolamellar cases but not in other tumor types for both methods indicating that detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma.", - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 260, - "name": "DNAJB1-PRKACA is specific for fibrolamellar carcinoma.", - "citation": "Graham et al., 2015, Mod. Pathol.", - "citation_id": "25698061", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25698061", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 6 - }, - "journal": "Mod. Pathol.", - "full_journal_title": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 31, - "phenotypes": [] - }, - { - "id": 1643, - "name": "EID1643", - "description": "A DNAJB1:PRKACA fusion transcript was detected at very high expression levels by RNA-Seq in a case of mixed fibrolamellar hepatocellular carcinoma. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed that the fusion was detectable in conventional components. An expanded screen of 112 additional HCC samples and 44 adjacent non-tumor liver samples was positive for a third case of HCC with both conventional and fibrolamellar features but negative for all conventional HCC and adjacent non-tumor liver samples.", - "disease": { - "id": 2961, - "name": "Mixed Fibrolamellar Hepatocellular Carcinoma", - "display_name": "Mixed Fibrolamellar Hepatocellular Carcinoma", - "doid": "0080182", - "url": "http://www.disease-ontology.org/?id=DOID:0080182" - }, - "drugs": [], - "rating": 4, - "evidence_level": "C", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1089, - "name": "A genomic case study of mixed fibrolamellar hepatocellular carcinoma.", - "citation": "Griffith et al., 2016, Ann. Oncol.", - "citation_id": "27029710", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27029710", - "open_access": true, - "pmc_id": "PMC4880064", - "publication_date": { - "year": 2016, - "month": 6 - }, - "journal": "Ann. Oncol.", - "full_journal_title": "Annals of oncology : official journal of the European Society for Medical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 31, - "phenotypes": [] - } - ], - "variant_groups": [], - "assertions": [ - { - "id": 24, - "type": "assertion", - "name": "AID24", - "summary": "DNAJB1-PRKACA fusion is highly sensitive and specific for diagnosis of fibrolamellar hepatocellular carcinoma", - "description": "A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA, resulting from a ~400kb genomic deletion, has been reported has highly recurrent in fibrolamellar HCC. Detection of this fusion by RNAseq, RT-PCR and FISH has subsequently shown this fusion to be highly sensitive and specific for diagnosis of fibrolamellar HCC and mixed fibrolamellar HCC. Several hundred fibrolamellar HCC, non-FL HCC or non-malignant tissues have now been assayed to demonstrate this.", - "gene": { - "name": "PRKACA", - "id": 17 - }, - "variant": { - "name": "DNAJB1-PRKACA", - "id": 31 - }, - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "evidence_type": "Diagnostic", - "evidence_direction": "Supports", - "clinical_significance": "Positive", - "fda_regulatory_approval": false, - "status": "accepted" - } - ], - "variant_aliases": [], - "hgvs_expressions": [], - "clinvar_entries": [], - "allele_registry_id": null - }, - "ASSERTIONS": [ - { - "id": 24, - "type": "assertion", - "name": "AID24", - "summary": "DNAJB1-PRKACA fusion is highly sensitive and specific for diagnosis of fibrolamellar hepatocellular carcinoma", - "description": "A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA, resulting from a ~400kb genomic deletion, has been reported has highly recurrent in fibrolamellar HCC. Detection of this fusion by RNAseq, RT-PCR and FISH has subsequently shown this fusion to be highly sensitive and specific for diagnosis of fibrolamellar HCC and mixed fibrolamellar HCC. Several hundred fibrolamellar HCC, non-FL HCC or non-malignant tissues have now been assayed to demonstrate this.", - "gene": { - "name": "PRKACA", - "id": 17 - }, - "variant": { - "name": "DNAJB1-PRKACA", - "id": 31 - }, - "disease": { - "id": 44, - "name": "Fibrolamellar Carcinoma", - "display_name": "Fibrolamellar Carcinoma", - "doid": "5015", - "url": "http://www.disease-ontology.org/?id=DOID:5015" - }, - "drugs": [], - "evidence_type": "Diagnostic", - "evidence_direction": "Supports", - "clinical_significance": "Positive", - "fda_regulatory_approval": false, - "status": "accepted" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/EID93.json b/analysis/civic/examples/harvester/EID93.json deleted file mode 100644 index d966bad8..00000000 --- a/analysis/civic/examples/harvester/EID93.json +++ /dev/null @@ -1,2873 +0,0 @@ -{ - "EVIDENCE": { - "id": 93, - "name": "EID93", - "description": "This was a Phase I and II study (NCT01072175) of dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy in patients with metastatic melanoma. \n\nCutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination therapy in contrast to 19% in those receiving monotherapy (P = 0.09).\n\nOf 162 patients with V600E or V600K mutation, 108 were given combination therapy and 54 monotherapy.\n\nAfter 1 year, 41% of patients in the combination group were alive and progression free whereas this was 9% in the monotherapy group (P<0.001).\n\n\nMedian progression-free survival was 9.4 months with combination and 5.8 months with monotherapy. Hazard ratio for progression or death was 0.39 (95% CI, 0.25 to 0.62; P<0.001).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 103, - "name": "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.", - "citation": "Flaherty et al., 2012, N. Engl. J. Med.", - "citation_id": "23020132", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23020132", - "open_access": true, - "pmc_id": "PMC3549295", - "publication_date": { - "year": 2012, - "month": 11 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01072175", - "name": "Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212", - "description": "This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01072175" - } - ] - }, - "variant_id": 17, - "phenotypes": [], - "assertions": [ - { - "id": 12, - "type": "assertion", - "name": "AID12", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "rejected" - } - ], - "gene_id": 5 - }, - "GENE": { - "id": 5, - "name": "BRAF", - "entrez_id": 673, - "description": "BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer.\n\nOncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors.\nClass 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors.\nClass 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors.\nClass 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase.", - "variants": [ - { - "name": "V600E", - "id": 12, - "evidence_items": { - "accepted_count": 88, - "rejected_count": 7, - "submitted_count": 79 - } - }, - { - "name": "T599dup", - "id": 1298, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "Mutation", - "id": 399, - "evidence_items": { - "accepted_count": 12, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600_S605delinsDV", - "id": 3241, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600", - "id": 17, - "evidence_items": { - "accepted_count": 22, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E and AMPLIFICATION", - "id": 14, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G496A", - "id": 2221, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "AKAP9-BRAF", - "id": 184, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K483M", - "id": 581, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "intron 10 rearrangement", - "id": 2226, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "CUX1-BRAF", - "id": 2229, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "intron 9 rearrangement", - "id": 2225, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "PAPSS1-BRAF", - "id": 286, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "TRIM24-BRAF", - "id": 287, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "WASFL-BRAF", - "id": 2228, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "AMPLIFICATION", - "id": 1269, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "WILD TYPE", - "id": 426, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "PPFIBP2-BRAF", - "id": 617, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "BRAF-CUL1", - "id": 656, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "MACF1-BRAF", - "id": 2227, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "ZKSCAN1-BRAF", - "id": 657, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "NRF1-BRAF", - "id": 2883, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "APC", - "id": 842, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 1, - "submitted_count": 0 - } - }, - { - "name": "N581S", - "id": 1186, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600G", - "id": 1199, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "A728V", - "id": 1198, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K601", - "id": 2765, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L597", - "id": 2766, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 4 - } - }, - { - "name": "V600L", - "id": 1404, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600M", - "id": 1405, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594", - "id": 2767, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G596", - "id": 2768, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "DELNVTAP", - "id": 1663, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G466A", - "id": 1196, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "AGK-BRAF", - "id": 285, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G469", - "id": 2822, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E/K and AMPLIFICATION", - "id": 2361, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594K", - "id": 2398, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "Non-V600", - "id": 2408, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "P731T", - "id": 2224, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G606E", - "id": 2223, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G466V", - "id": 2222, - "evidence_items": { - "accepted_count": 4, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "DEL 485-490", - "id": 522, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594A", - "id": 579, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594V", - "id": 580, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600K", - "id": 563, - "evidence_items": { - "accepted_count": 8, - "rejected_count": 0, - "submitted_count": 10 - } - }, - { - "name": "L597S", - "id": 582, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "K601E", - "id": 584, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "L597V", - "id": 585, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L597Q", - "id": 583, - "evidence_items": { - "accepted_count": 3, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "L505H", - "id": 658, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G596C", - "id": 694, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "G469V", - "id": 841, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469A", - "id": 992, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V600R", - "id": 991, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 7 - } - }, - { - "name": "G464V", - "id": 1106, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F595L", - "id": 1121, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469E", - "id": 993, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G469R", - "id": 840, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600_K601DELINSD", - "id": 1658, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "G596V", - "id": 1650, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G596R", - "id": 1627, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L597R", - "id": 288, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "D594N", - "id": 1107, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 5, - "submitted_count": 2 - } - }, - { - "name": "D594G", - "id": 611, - "evidence_items": { - "accepted_count": 9, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "EXON 15 MUTATION", - "id": 2650, - "evidence_items": { - "accepted_count": 2, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "BRAF fusions and mutations", - "id": 2639, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "KIAA1549-BRAF", - "id": 618, - "evidence_items": { - "accepted_count": 11, - "rejected_count": 1, - "submitted_count": 3 - } - }, - { - "name": "FAM131B-BRAF", - "id": 2656, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K439Q", - "id": 2775, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "K439T", - "id": 2776, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G466E", - "id": 2792, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L525R", - "id": 2793, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "T488_P492del", - "id": 2795, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "P490_Q494del", - "id": 2796, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594E", - "id": 2799, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "class 2 mutations", - "id": 2800, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "F247L", - "id": 2802, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "R558Q", - "id": 2803, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "L485F", - "id": 2804, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600_S602>DT", - "id": 2821, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "G593D", - "id": 2823, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V601E", - "id": 2825, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 2 - } - }, - { - "name": "N486_P490del", - "id": 2794, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 3 - } - }, - { - "name": "V600_K601>E", - "id": 2820, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "A598V", - "id": 2826, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "class 3 mutations", - "id": 2801, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "T599_V600insT", - "id": 2824, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "FAM73A-BRAF", - "id": 2987, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "D594H", - "id": 2832, - "evidence_items": { - "accepted_count": 0, - "rejected_count": 0, - "submitted_count": 1 - } - }, - { - "name": "V600E and V600M", - "id": 13, - "evidence_items": { - "accepted_count": 1, - "rejected_count": 0, - "submitted_count": 0 - } - }, - { - "name": "V600D", - "id": 11, - "evidence_items": { - "accepted_count": 5, - "rejected_count": 0, - "submitted_count": 0 - } - } - ], - "aliases": [ - "BRAF", - "B-raf", - "RAFB1", - "NS7", - "BRAF1", - "B-RAF1" - ], - "type": "gene" - }, - "VARIANT": { - "id": 17, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600", - "description": "BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 103, - "name": "protein_altering_variant", - "display_name": "Protein Altering Variant", - "so_id": "SO:0001818", - "description": "A sequence_variant which is predicted to change the protein encoded in the coding sequence.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001818" - } - ], - "civic_actionability_score": 460, - "coordinates": { - "chromosome": "7", - "start": 140453136, - "stop": 140453137, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": [ - { - "id": 88, - "name": "EID88", - "description": "In metastatic colorectal cancer patients with wildtype KRAS, BRAF mutations were associated with poor progression free survival regardless of treatment (panitumumab with best supportive care or best supportive care alone).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 28, - "name": "Panitumumab", - "ncit_id": "C1857", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 99, - "name": "Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer.", - "citation": "Peeters et al., 2013, Clin. Cancer Res.", - "citation_id": "23325582", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23325582", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 4, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 93, - "name": "EID93", - "description": "This was a Phase I and II study (NCT01072175) of dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy in patients with metastatic melanoma. \n\nCutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination therapy in contrast to 19% in those receiving monotherapy (P = 0.09).\n\nOf 162 patients with V600E or V600K mutation, 108 were given combination therapy and 54 monotherapy.\n\nAfter 1 year, 41% of patients in the combination group were alive and progression free whereas this was 9% in the monotherapy group (P<0.001).\n\n\nMedian progression-free survival was 9.4 months with combination and 5.8 months with monotherapy. Hazard ratio for progression or death was 0.39 (95% CI, 0.25 to 0.62; P<0.001).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 103, - "name": "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.", - "citation": "Flaherty et al., 2012, N. Engl. J. Med.", - "citation_id": "23020132", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23020132", - "open_access": true, - "pmc_id": "PMC3549295", - "publication_date": { - "year": 2012, - "month": 11 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01072175", - "name": "Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212", - "description": "This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01072175" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1407, - "name": "EID1407", - "description": "In the NCT00880321 trial using mutant BRAF inhibitor dabrafenib in solid tumors, 10 cases of melanoma brain metastases were assessed for dabrafenib response. In nine patients a decrease in size of metastases was seen, and in four cases a complete resolution of brain lesions was observed. This subset of patients had median progression free survival of 4.2 months.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 345, - "name": "Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.", - "citation": "Falchook et al., 2012, Lancet", - "citation_id": "22608338", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22608338", - "open_access": true, - "pmc_id": "PMC4109288", - "publication_date": { - "year": 2012, - "month": 5, - "day": 19 - }, - "journal": "Lancet", - "full_journal_title": "Lancet (London, England)", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT00880321", - "name": "A Phase I Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of GSK2118436 in Subjects With Solid Tumors", - "description": "BRF112680 is a first-time-in-human study to establish the recommended dose and schedule of the orally administered GSK2118436. The recommended dose and regimen will be selected based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after the treatment of subjects with solid tumors. This is a two-part study. Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. The recommended Part 2 dose will be expanded to up to 12 patients. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors. In addition, the effect of GSK2118436 on midazolam will be assessed in a subset of patients in Part 2. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT00880321" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1411, - "name": "EID1411", - "description": "The Combi-v (NCT01597908) open-label, randomized phase 3 trial had 704 patients with metastatic melanoma with a BRAF V600 mutation. Patients were randomized to receive either a combination of dabrafenib and trametinib or vemurafenib orally as first-line therapy. At preplanned interim analysis the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). Cutaneous squamous-cell carcinoma and keratoacanthoma occurred at 1% with combination-therapy and 18% in the vemurafenib group.", - "disease": { - "id": 206, - "name": "Skin Melanoma", - "display_name": "Skin Melanoma", - "doid": "8923", - "url": "http://www.disease-ontology.org/?id=DOID:8923" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 353, - "name": "Improved overall survival in melanoma with combined dabrafenib and trametinib.", - "citation": "Robert et al., 2015, N. Engl. J. Med.", - "citation_id": "25399551", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25399551", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2015, - "month": 1, - "day": 1 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01597908", - "name": "Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma", - "description": "This is a two-arm, open-label, randomised, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to vemurafenib. Subjects with histologically confirmed cutaneous melanoma that is either stage IIIc (unresectable) or stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 694 subjects will be randomised 1:1 (combination therapy:vemurafenib). The primary endpoint is overall survival (OS) for subjects receiving the combination therapy compared with those receiving vemurafenib.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01597908" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1415, - "name": "EID1415", - "description": "In clinical trial NCT01072175, 43 patients with BRAF V600 metastatic colorectal cancer (CRC) received mutant BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Only 12% of patients showed partial response or better, with one complete response lasting 36 months and ongoing after data cutoff. 56% of patients achieved stable disease. The median progression free survival (PFS) was 3.5 months, longer than the median PFS (2.5 months) reported for metastatic CRC treated with standard chemotherapy. The authors conclude that MAPK targeting in CRC is a valid approach that can produce meaningful responses but additional work is required to more effectively inhibit the pathway.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 959, - "name": "Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.", - "citation": "Corcoran et al., 2015, J. Clin. Oncol.", - "citation_id": "26392102", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26392102", - "open_access": true, - "pmc_id": "PMC4669588", - "publication_date": { - "year": 2015, - "month": 12, - "day": 1 - }, - "journal": "J. Clin. Oncol.", - "full_journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01072175", - "name": "Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212", - "description": "This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01072175" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1422, - "name": "EID1422", - "description": "In a randomized phase 3 study, previously untreated advanced or metastatic BRAF V600 mutation-positive melanoma patients treated with combination vemurafenib and cobimetinib showed improved progression free survival (9.9 vs 6.2 months), increased rate of complete or partial response (68% vs 45%), and improved overall survival at 9 months ( 81% vs 73%) compared to the vemurafenib and placebo control group.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - }, - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 963, - "name": "Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.", - "citation": "Larkin et al., 2014, N. Engl. J. Med.", - "citation_id": "25265494", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25265494", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 11, - "day": 13 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01689519", - "name": "A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma", - "description": "To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01689519" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1574, - "name": "EID1574", - "description": "Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 20 patients with non-small-cell-lung cancer (17 with BRAF V600E, one with BRAF V600G and one with BRAF V600 unknown status), 19 were evaluable and the response rate to vemurafenib was 42%, tumor regression was observed in 14/19 patients, progression-free survival was 7.3 months, and 12-month overall survival was 66%.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1575, - "name": "EID1575", - "description": "Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 14 patients with Langerhans\u2019-cell histiocytosis, 43% of patients had a response to vemurafenib (1 complete and 5 partial responses), disease regression was observed in 12/14 patients, all patients detailed improvement in disease-related symptoms, 0 patients had progressive disease during treatment, 12-month progression free survival was 91%, and overall survival rate was 100%.\nAmong all 18 patients with Erdheim-Chester disease or Langerhans histiocytosis, 94% had BRAF V600E mutations and the remaining 6 percent (1 patient) had an unknown V600 mutation.", - "disease": { - "id": 2136, - "name": "Langerhans-cell Histiocytosis", - "display_name": "Langerhans-cell Histiocytosis", - "doid": "2571", - "url": "http://www.disease-ontology.org/?id=DOID:2571" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1576, - "name": "EID1576", - "description": "Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 10 patients with colorectal cancer (80% BRAF V600E, 20% V600 unknown status), no responses were observed and overall survival was 9.3 months with a median progression-free survival of 4.5 months.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1598, - "name": "EID1598", - "description": "Patients with BRAF-V600 mutated cancers were identified (n=122) and subsequently underwent targeted therapy. 27 patients with colorectal cancer were treated with vemurafenib and cetuximab (N=24 with BRAF V600E mutation, N=3 with V600 unknown status). One response was observed; however, approximately half the patients had tumor regression that did not meet the standard criteria for a partial response. Median progression-free survival and overall survival for patients receiving combination therapy were 3.7 months (95% CI, 1.8 to 5.1) and 7.1 months (95% CI, 4.4 to not reached), respectively. Patients were heavily pretreated, with a median of two lines of previous therapy (range, one to six).", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 2, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Does Not Support", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1750, - "name": "EID1750", - "description": "Patients who had histologically confirmed, unresectable stage IIIC or IV cutaneous melanoma with a V600E or V600K BRAF mutation were eligible for the study. 322 eligible patients (281 with the V600E mutation, 40 with the V600K mutation, and 1 with both mutations) in a 2:1 ratio to receive oral trametinib (2 mg once daily) or intravenous chemotherapy consisting of either dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter), at the discretion of the investigator, every 3 weeks. The primary end point was progression-free survival; secondary end points included overall survival, overall response rate, duration of response, and safety. Treatment continued until disease progression, death, or withdrawal from the study. In the intention-to-treat population, the median duration of progression-free survival was 4.8 months in the trametinib group as compared with 1.5 months in the chemotherapy group (hazard ratio for progression, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). The 6-month overall survival rate in the intention-to-treat population was 81% in the trametinib group and 67% in the chemotherapy group.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1210, - "name": "Improved survival with MEK inhibition in BRAF-mutated melanoma.", - "citation": "Flaherty et al., 2012, N. Engl. J. Med.", - "citation_id": "22663011", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22663011", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2012, - "month": 7, - "day": 12 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01245062", - "name": "GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma", - "description": "This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01245062" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 5905, - "name": "EID5905", - "description": "Eight patients with BRAF V600 (7 with V600E, 1 with V600 unknown) mutated cholangiocarcinoma received vemurafenib. Only one patients showed partial response and duration of response of this patient was longer than 12 months.", - "disease": { - "id": 29, - "name": "Cholangiocarcinoma", - "display_name": "Cholangiocarcinoma", - "doid": "4947", - "url": "http://www.disease-ontology.org/?id=DOID:4947" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 1040, - "name": "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.", - "citation": "Hyman et al., 2015, N. Engl. J. Med.", - "citation_id": "26287849", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/26287849", - "open_access": true, - "pmc_id": "PMC4971773", - "publication_date": { - "year": 2015, - "month": 8, - "day": 20 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01524978", - "name": "A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers", - "description": "This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01524978" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6044, - "name": "EID6044", - "description": "In this double-blind, randomized, placebo-controlled, multicentre study, adult patients with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) to receive cobimetinib or placebo, in combination with oral vemurafenib. Progression-free survival was the primary endpoint.\nBetween Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). Investigator-assessed median progression-free survival was 12.3 months for cobimetinib and vemurafenib versus 7.2 months for placebo and vemurafenib (HR 0.58 [95% CI 0.46-0.72], p<0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib versus 17.4 months for placebo and vemurafenib (HR 0.70, 95% CI 0.55-0.90; p=0.005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - }, - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2441, - "name": "Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.", - "citation": "Ascierto et al., 2016, Lancet Oncol.", - "citation_id": "27480103", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/27480103", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2016, - "month": 9 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01689519", - "name": "A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma", - "description": "To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01689519" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6046, - "name": "EID6046", - "description": "In a Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab, Twenty-six patients with refractory BRAF V600 mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab). Confirmed overall response rates of 19% were observed and median progression-free survival was 3.7 months.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2442, - "name": "A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.", - "citation": "van Geel et al., 2017, Cancer Discov", - "citation_id": "28363909", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28363909", - "open_access": true, - "pmc_id": "PMC5546207", - "publication_date": { - "year": 2017 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6047, - "name": "EID6047", - "description": "In a phase Ib dose-escalation study of encorafenib, cetuximab and alpelisib, twenty-eight patients with refractory BRAF V600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab) with a PI3K\u03b1 inhibitor (alpelisib). Confirmed overall response rates of 18% were observed and median progression-free survival was 4.2 months", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 570, - "name": "Alpelisib", - "ncit_id": "C94214", - "aliases": [ - "Piqray", - "Phosphoinositide 3-kinase Inhibitor BYL719", - "BYL719" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2442, - "name": "A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.", - "citation": "van Geel et al., 2017, Cancer Discov", - "citation_id": "28363909", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28363909", - "open_access": true, - "pmc_id": "PMC5546207", - "publication_date": { - "year": 2017 - }, - "journal": "Cancer Discov", - "full_journal_title": "Cancer discovery", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6180, - "name": "EID6180", - "description": "Combination Dabrafenib and Trametinib treatment was assessed for adjuvant treatment of stage III resected BRAF V600 mutant melanoma in the COMBI-AD trial NCT01682083. Patients were treated with combination therapy or placebo for 12 months. The estimated 3-year rate of relapse-free survival was 58% in the treated group and 39% in the placebo group with hazard ratio for relapse or death of 0.47 (95% CI, 0.39 to 0.58; P<0.001). 3-year overall survival rate for treated group was 86%, and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42-0.79; P=0.0006). The level of improvement observed did not cross the prespecified interim analysis boundary of P=0.000019. Distant metastasis-free survival and freedom from relapse was higher in the combination-treated group.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2475, - "name": "Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.", - "citation": "Long et al., 2017, N. Engl. J. Med.", - "citation_id": "28891408", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/28891408", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017, - "day": 9 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01682083", - "name": "A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection.", - "description": "This is a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma will be screened for eligibility. Subjects will be randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or two placebos for 12 months.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01682083" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6937, - "name": "EID6937", - "description": "In this Phase III trial (NCT01584648 COMBI-d), 423 previously untreated patients with unresectable stage IIIC or IV BRAF V600E or V600K mutant melanoma received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival with secondary endpoints including disease response. The hazard ratio for progression or death in the dabrafenib\u2013trametinib group was 0.75 (95% confidence interval, 0.57 to 0.99; P=0.03). Of 210 patients in the dabrafenib + trametinib group, 67% of patients had a response, which was 16 percentage points higher than in the dabrafenib-alone group (95% CI, 6 to 25; P=0.002).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - }, - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - } - ], - "rating": 5, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2671, - "name": "Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.", - "citation": "Long et al., 2014, N. Engl. J. Med.", - "citation_id": "25265492", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25265492", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 11, - "day": 13 - }, - "journal": "N. Engl. J. Med.", - "full_journal_title": "The New England journal of medicine", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01584648", - "name": "A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma", - "description": "This is a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to dabrafenib administered with a trametinib placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 340 subjects will be randomized 1:1 (combination therapy: dabrafenib monotherapy). Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). The primary endpoint is investigator-assessed, progression-free survival for subjects receiving the combination therapy compared with those receiving dabrafenib monotherapy. Subjects will be followed for overall survival; crossover will not be permitted.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01584648" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 6966, - "name": "EID6966", - "description": "In this Phase 1b study, 129 patients with unresectable or metastatic melanoma were verified for BRAF V600 mutation using the cobas 4800 mutation test were selected who had progressed on vemurafenib (66 patients) or never received BRAF inhibitor (63 patients). The combination of vemurafenib and cobimetinib was deemed safe and tolerable. Confirmed objective responses were seen in 15% of vemurafenib progressed patients and median progression-free survival was 2.8 months (95% CI 2\u00b76\u20133\u00b74). Confirmed objective responses were seen in 87% of patients who had never received BRAF inhibitor, including 10% with complete response. Median progression-free survival was 13.7 months (95% CI 10\u00b71\u201317\u00b75). The majority of patients had BRAF V600E mutation. Post-hoc sequencing of 94 tumor samples indicated seven tumors with a mutation other than BRAF V600E.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - }, - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2688, - "name": "Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study.", - "citation": "Ribas et al., 2014, Lancet Oncol.", - "citation_id": "25037139", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/25037139", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2014, - "month": 8 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01271803", - "name": "A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma", - "description": "This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01271803" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 7287, - "name": "EID7287", - "description": "In a phase 3 trial, patients with melanoma with BRAF V600E or V600K mutation were randomly assigned to encorafenib plus binimetinib or vemurafenib or encorafenib.\nmPFS was 14\u00b79 months (95% CI 11\u00b70-18\u00b75) in the encorafenib plus binimetinib group and 7\u00b73 months (5\u00b76-8\u00b72) in the vemurafenib group (hazard ratio [HR] 0\u00b754, 95% CI 0\u00b741-0\u00b771; two-sided p<0\u00b70001)", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 485, - "name": "Binimetinib", - "ncit_id": "C84865", - "aliases": [ - "Mektovi", - "MEK162", - "ARRY-438162", - "ARRY-162" - ] - } - ], - "rating": 5, - "evidence_level": "A", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2874, - "name": "Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.", - "citation": "Dummer et al., 2018, Lancet Oncol.", - "citation_id": "29573941", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/29573941", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2018 - }, - "journal": "Lancet Oncol.", - "full_journal_title": "The Lancet. Oncology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01909453", - "name": "Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma", - "description": "This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized. Part 1: Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms: 1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm) 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or 3. vemurafenib 960 mg BID (denoted as vemurafenib arm) Part 2: Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms: 1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01909453" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 7355, - "name": "EID7355", - "description": "A randomized clinical trial was done with metastatic colorectal cancer (mCRC) patients (50 in the control group, 49 in the experimental group) with BRAF V600 mutations and RAS wild type that were enrolled from December 2014 to April 2016. The patients were randomized into groups with irinotecan and cetuximab with vemurafenib (VIC group) or without (IC group). The VIC group showed an improvement of progression of free survival (HR 0.42, 95% CI: 0.26 to 0.66, p < 0.001) with a median value of 4.4 months compared to 2.0 months for the IC group. In addition, for the VIC group, there was a 16% drug response rate while the IC group had a 4% drug response rate (p-value = 0.08). Some grade 3/4 adverse events were higher in the experimental arm, and skin toxicity and fatigue showed no increase.", - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - }, - { - "id": 101, - "name": "Irinotecan", - "ncit_id": "C62040", - "aliases": [ - "[1,4'-bipiperidine]-1'-carboxylic Acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl Ester", - "7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin", - "(+)-7-ethyl-10-hydroxycamptothecine 10-[1,4'-bipiperidine]-1'-carboxylate", - "(+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinol-3,14,(4H,12H)-dione" - ] - }, - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Combination", - "status": "accepted", - "type": "evidence", - "source": { - "id": 2905, - "name": "Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).", - "citation": "Scott Kopetz, 2017, ASCO Annual Meeting, Abstract 3505", - "citation_id": "147167", - "source_type": "ASCO", - "asco_abstract_id": 3505, - "source_url": "https://meetinglibrary.asco.org/record/147167/abstract", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2017 - }, - "journal": "J Clin Oncol 35, 2017 (suppl; abstr 3505)", - "full_journal_title": "Dermatosen in Beruf und Umwelt. Occupation and environment", - "status": "fully curated", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT02164916", - "name": "S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer", - "description": "This randomized phase II trial studies how well irinotecan hydrochloride and cetuximab with or without vemurafenib works in treating patients with colorectal cancer that has spread to nearby tissue or lymph nodes, that has spread to other places in the body, or cannot be removed by surgery. Irinotecan hydrochloride and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block the ability of tumor cells to grow and spread. It is not yet known whether irinotecan hydrochloride and cetuximab are more effective with or without vemurafenib in treating colorectal cancer.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT02164916" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 1000, - "name": "EID1000", - "description": "Phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766. 2 of 2 patients with BRAF mutant melanoma had moderate progressive disease (despite receiving the highest doses administered in the study).", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 394, - "name": "Refametinib", - "ncit_id": "C74059", - "aliases": [ - "RDEA119", - "MEK Inhibitor RDEA119", - "BAY86-9766", - "BAY 869766" - ] - } - ], - "rating": 2, - "evidence_level": "C", - "evidence_type": "Predictive", - "clinical_significance": "Resistance", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 690, - "name": "Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.", - "citation": "Weekes et al., 2013, Clin. Cancer Res.", - "citation_id": "23434733", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/23434733", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2013, - "month": 3, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 8034, - "name": "EID8034", - "description": "This clinical trial used a cohort of 32 pediatric low grade glioma (pLGG) patients. The primary endpoint of this study was objective response rate (ORR). In this study, an ORR of 44% and a 1-year progression free survival rate of 85% was reported. Approximately half of the patients had an ongoing treatment response at the end of the study, while only two had progressive disease. Although the study cohort was on the smaller side, this provides evidence that treatment BRAF V600-mutant pLGG patients with Dabrafenib could be beneficial. Being a clinical trial, the study was not well controlled.", - "disease": { - "id": 3048, - "name": "Pediatric Low-grade Glioma", - "display_name": "Pediatric Low-grade Glioma", - "doid": "0080830", - "url": "http://www.disease-ontology.org/?id=DOID:0080830" - }, - "drugs": [ - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "submitted", - "type": "evidence", - "source": { - "id": 3124, - "name": "Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study.", - "citation": "Hargrave et al., 2019, Clin. Cancer Res.", - "citation_id": "31811016", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/31811016", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2019, - "month": 12, - "day": 15 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "submitted", - "is_review": false, - "clinical_trials": [ - { - "nct_id": "NCT01677741", - "name": "A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects", - "description": "This is a 2-part, study to determine the safety, tolerability and pharmacokinetics of oral dabrafenib in children and adolescent subjects with advanced BRAF V600 mutation-positive solid tumors. Part 1 (dose escalation study) will identify the recommended Part 2 (tumor-specific expansion study) dose and regimen using a dose-escalation procedure. Approximately 6 to 18 subjects will participate in Part 1 and will receive a starting dose of 3 mg/kg and dose will deescalate or escalate between 1.5 milligram (mg)/kilogram (kg) and 6 mg/kg. Up to 6 subjects will be enrolled at one dose level dependent upon the number of subjects at the current dose level, the number of subjects who have experienced a dose limiting toxicity (DLT) at the current dose level, and the number of subjects enrolled but with data pending at the current dose level. Escalation may proceed until either a maximum tolerated dose (MTD) is established, or until the dose in which the median pharmacokinetic parameters consistent with exposure in adults are achieved. Cohorts may be added in order to evaluate additional dose levels. Part 2 consists of four disease-specific cohorts of subjects with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis [LCH], and other tumors such as melanoma and papillary thyroid carcinoma [PTC]). Each cohort will enroll at least 10 subjects with a pre-dose and at least 1 post-dose disease assessment. In both the parts of the study, on Day 1, a single first dose will be administered, and repeat dosing will begin on Day 2. PK sampling will be performed on Day 1 and Day 15 for subjects >=25 kg in weight. For subjects <25 kg and >=10 kg in weight, blood samples for PK analysis will be collected on Day 1 and Day 15. For subjects <10kg in weight, blood samples for PK analysis will be collected after repeated administration on Day 15 only. Safety and tolerability will be assessed throughout the study. Treatment with dabrafenib will be continued until disease progression or until no clinical benefit or development of an unacceptable toxicity, or until they withdraw consent or begin a new therapy. At the end of treatment, a final study visit will occur.", - "clinical_trial_url": "https://clinicaltrials.gov/show/NCT01677741" - } - ] - }, - "variant_id": 17, - "phenotypes": [] - }, - { - "id": 30, - "name": "EID30", - "description": "BRAF mutations are associated with melanoma arising in non-chronic sun damaged skin and with superficial spreading melanoma.", - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Diagnostic", - "clinical_significance": "Positive", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 71, - "name": "Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis.", - "citation": "Lee et al., 2011, Br. J. Dermatol.", - "citation_id": "21166657", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/21166657", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 4 - }, - "journal": "Br. J. Dermatol.", - "full_journal_title": "The British journal of dermatology", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 17, - "phenotypes": [] - } - ], - "variant_groups": [ - { - "id": 5, - "name": "Other V600's", - "description": "While BRAF V600E is nearly ubiquitous in many cancer types, other V600 variants have also been observed and studied to a lesser degree. At first approximation, many of these variants seem to behave similarly to V600E, and treatment with dabrafenib has been shown to be effective. ", - "variants": [ - { - "id": 11, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600D", - "description": "Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 47, - "coordinates": { - "chromosome": "7", - "start": 140453135, - "stop": 140453136, - "reference_bases": "CA", - "variant_bases": "AT", - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 13, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600E and V600M", - "description": "A case study of a single patient harboring both a V600E and a V600M mutation, dabrafenib was shown to acheive clinical response.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 7.5, - "coordinates": { - "chromosome": "7", - "start": 140453135, - "stop": 140453137, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 17, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600", - "description": "BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 103, - "name": "protein_altering_variant", - "display_name": "Protein Altering Variant", - "so_id": "SO:0001818", - "description": "A sequence_variant which is predicted to change the protein encoded in the coding sequence.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001818" - } - ], - "civic_actionability_score": 460, - "coordinates": { - "chromosome": "7", - "start": 140453136, - "stop": 140453137, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 288, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "L597R", - "description": "", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 12, - "coordinates": { - "chromosome": "7", - "start": 140453145, - "stop": 140453145, - "reference_bases": "A", - "variant_bases": "C", - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "id": 563, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600K", - "description": "", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 107.5, - "coordinates": { - "chromosome": "7", - "start": 140453136, - "stop": 140453137, - "reference_bases": "AC", - "variant_bases": "TT", - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - } - } - ], - "type": "variant_group" - } - ], - "assertions": [], - "variant_aliases": [ - "VAL600" - ], - "hgvs_expressions": [], - "clinvar_entries": [ - "40389", - "44815", - "376289", - "44816", - "13961", - "376288" - ], - "allele_registry_id": null - }, - "ASSERTIONS": [ - { - "id": 12, - "type": "assertion", - "name": "AID12", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "rejected" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/amplification.json b/analysis/civic/examples/harvester/amplification.json deleted file mode 100644 index 8cc4e7bb..00000000 --- a/analysis/civic/examples/harvester/amplification.json +++ /dev/null @@ -1,107 +0,0 @@ -{ - "id": 190, - "entrez_name": "EGFR", - "entrez_id": 1956, - "name": "Amplification", - "description": "", - "gene_id": 19, - "type": "variant", - "variant_types": [ - { - "id": 123, - "name": "transcript_amplification", - "display_name": "Transcript Amplification", - "so_id": "SO:0001889", - "description": "A feature amplification of a region containing a transcript.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001889" - } - ], - "civic_actionability_score": 133, - "coordinates": { - "chromosome": "7", - "start": 55086794, - "stop": 55279321, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000275493.2", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": { - "id": 5924, - "name": "EID5924", - "description": "The result of the analysis found that EGFR gene copy number was associated with increased OS and PFS, supporting the idea that EGFR gene copy number is a biomarker for response to EGFR-TKI therapy in patients with advanced NSCLC.", - "disease": { - "id": 8, - "name": "Lung Non-small Cell Carcinoma", - "display_name": "Lung Non-small Cell Carcinoma", - "doid": "3908", - "url": "http://www.disease-ontology.org/?id=DOID:3908" - }, - "drugs": [ - { - "id": 14, - "name": "Gefitinib", - "ncit_id": "C1855", - "aliases": [ - "ZD1839", - "ZD 1839", - "N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) Propoxy]-4-quinazolinamine", - "Iressa", - "4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline" - ] - }, - { - "id": 15, - "name": "Erlotinib", - "ncit_id": "C65530", - "aliases": [] - } - ], - "rating": 4, - "evidence_level": "B", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 650, - "name": "EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer.", - "citation": "Dahabreh et al., 2011, Ann. Oncol.", - "citation_id": "20826716", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/20826716", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2011, - "month": 3 - }, - "journal": "Ann. Oncol.", - "full_journal_title": "Annals of oncology : official journal of the European Society for Medical Oncology / ESMO", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 190, - "phenotypes": [] - }, - "variant_groups": [], - "assertions": [], - "variant_aliases": [], - "hgvs_expressions": [ - "N/A" - ], - "clinvar_entries": [ - "N/A" - ], - "allele_registry_id": null -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/bcr-abl.json b/analysis/civic/examples/harvester/bcr-abl.json deleted file mode 100644 index d1d767ab..00000000 --- a/analysis/civic/examples/harvester/bcr-abl.json +++ /dev/null @@ -1,125 +0,0 @@ -{ - "id": 1, - "entrez_name": "ABL1", - "entrez_id": 25, - "name": "BCR-ABL", - "description": "The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors.", - "gene_id": 4, - "type": "variant", - "variant_types": [ - { - "id": 120, - "name": "transcript_fusion", - "display_name": "Transcript Fusion", - "so_id": "SO:0001886", - "description": "A feature fusion where the deletion brings together transcript regions.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001886" - } - ], - "civic_actionability_score": 255.5, - "coordinates": { - "chromosome": "22", - "start": 23522397, - "stop": 23632600, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000305877.8", - "chromosome2": "9", - "start2": 133729451, - "stop2": 133763063, - "representative_transcript2": "ENST00000318560.5", - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": { - "id": 7838, - "name": "EID7838", - "description": "In an in vitro study, six CML cell lines expressing the BCR-ABL1 fusion protein showed sensitivity to nilotinib (IC50: 24.3-84.5 nM), dasatinib (IC50: 1.5-10.9 nM), and bafetinib (IC50: 11.8-87.7 nM). When comparing potency of these treatments against the 6 CML cell lines, dasatinib, nilotinib and bafetinib were on average 98.6, 9.85 and 16.4 times more potent than imatinib. Sensitivity was determined by assessing cell proliferation using the MTT assay.", - "disease": { - "id": 4, - "name": "Chronic Myeloid Leukemia", - "display_name": "Chronic Myeloid Leukemia", - "doid": "8552", - "url": "http://www.disease-ontology.org/?id=DOID:8552" - }, - "drugs": [ - { - "id": 625, - "name": "Bafetinib", - "ncit_id": "C62516", - "aliases": [ - "NS-187", - "INNO-406", - "Dual Bcr-Abl/Lyn Tyrosine Kinase Inhibitor INNO-406", - "CNS-9", - "Benzamide, N-[3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl]-4-[[(3S)-3- (dimethylamino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)-" - ] - }, - { - "id": 20, - "name": "Dasatinib", - "ncit_id": "C38713", - "aliases": [ - "Sprycel", - "Dasatinib Monohydrate", - "Dasatinib Hydrate", - "BMS-354825", - "5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-, Monohydrate" - ] - }, - { - "id": 13, - "name": "Nilotinib", - "ncit_id": "C48375", - "aliases": [ - "AMN 107 Base Form", - "4-Methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-N-(5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide" - ] - } - ], - "rating": 3, - "evidence_level": "D", - "evidence_type": "Predictive", - "clinical_significance": "Sensitivity/Response", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": "Substitutes", - "status": "accepted", - "type": "evidence", - "source": { - "id": 1621, - "name": "Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines.", - "citation": "Deguchi et al., 2008, Leuk. Res.", - "citation_id": "18191450", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/18191450", - "open_access": null, - "pmc_id": null, - "publication_date": { - "year": 2008, - "month": 6 - }, - "journal": "Leuk. Res.", - "full_journal_title": "Leukemia research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 1, - "phenotypes": [] - }, - "variant_groups": [], - "assertions": [], - "variant_aliases": [ - "T(9;22)(Q34;Q11)", - "BCR-ABL1" - ], - "hgvs_expressions": [ - "N/A" - ], - "clinvar_entries": [ - "N/A" - ], - "allele_registry_id": null -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/civic_harvester_example.py b/analysis/civic/examples/harvester/civic_harvester_example.py deleted file mode 100644 index f79a70b9..00000000 --- a/analysis/civic/examples/harvester/civic_harvester_example.py +++ /dev/null @@ -1,78 +0,0 @@ -"""Create an example json file for CIViC Harvester.""" -import json - -from metakb import APP_ROOT, PROJECT_ROOT -from metakb.harvesters import CivicHarvester - - -def create_evidence_examples(data): - """Create five CIViC evidence examples.""" - evidence_items = list() - for i in range(len(data["evidence"])): - if data["evidence"][i]["assertions"]: - evidence_items.append(data["evidence"][i]) - if len(evidence_items) == 6: - break - - for evidence_item in evidence_items: - variant_id = evidence_item["variant_id"] - gene_id = evidence_item["gene_id"] - assertions = evidence_item["assertions"] - - for v in data["variants"]: - if v["id"] == variant_id: - variant = v - - for g in data["genes"]: - if g["id"] == gene_id: - gene = g - - with open( - f"{PROJECT_ROOT}/analysis/civic/examples/harvester/" - f"{evidence_item['name']}.json", - "w+", - ) as f: - example = { - "EVIDENCE": evidence_item, - "GENE": gene, - "VARIANT": variant, - "ASSERTIONS": assertions, - } - - json.dump(example, f, indent=4) - - -def create_variant_examples(data): - """Create variant examples for BRAF600E, BCR-ABL Variant, - TP53 Loss (of function), and EGFR Amplification. - """ - variants_ids = [12, 1, 221, 190] - variants = list() - for i in range(len(data["variants"])): - if data["variants"][i]["id"] in variants_ids: - variants.append(data["variants"][i]) - - for variant in variants: - with open( - f"{PROJECT_ROOT}/analysis/civic/examples/harvester/" - f"{variant['name'].lower()}.json", - "w+", - ) as f: - variant["evidence_items"] = variant["evidence_items"][0] - f.write(json.dumps(variant, indent=4)) - - -if __name__ == "__main__": - c = CivicHarvester() - c.harvest() - latest = sorted( - (APP_ROOT / "data" / "civic" / "harvester").glob("civic_harvester_*.json") - )[-1] # noqa: E501 - with open(latest, "r") as f: - civic_data = json.load(f) - - civic_ex_dir = PROJECT_ROOT / "analysis" / "civic" / "examples" / "harvester" - civic_ex_dir.mkdir(exist_ok=True, parents=True) - - create_evidence_examples(civic_data) - create_variant_examples(civic_data) diff --git a/analysis/civic/examples/harvester/deleterious mutation.json b/analysis/civic/examples/harvester/deleterious mutation.json deleted file mode 100644 index c336be5b..00000000 --- a/analysis/civic/examples/harvester/deleterious mutation.json +++ /dev/null @@ -1,85 +0,0 @@ -{ - "id": 221, - "entrez_name": "TP53", - "entrez_id": 7157, - "name": "Deleterious Mutation", - "description": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", - "gene_id": 45, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 78, - "coordinates": { - "chromosome": "17", - "start": 7571720, - "stop": 7590856, - "reference_bases": null, - "variant_bases": null, - "representative_transcript": "ENST00000269305.4", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": { - "id": 517, - "name": "EID517", - "description": "In a study of 74 patients with head and neck squamous cell carcinoma, those with disruptive mutations in TP53 had shorter overall survival and a higher rate of locoregional recurrence than those without mutations or with nondisruptive mutations.", - "disease": { - "id": 37, - "name": "Head And Neck Squamous Cell Carcinoma", - "display_name": "Head And Neck Squamous Cell Carcinoma", - "doid": "5520", - "url": "http://www.disease-ontology.org/?id=DOID:5520" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 320, - "name": "TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.", - "citation": "Skinner et al., 2012, Clin. Cancer Res.", - "citation_id": "22090360", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/22090360", - "open_access": true, - "pmc_id": "PMC3251726", - "publication_date": { - "year": 2012, - "month": 1, - "day": 1 - }, - "journal": "Clin. Cancer Res.", - "full_journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 221, - "phenotypes": [] - }, - "variant_groups": [], - "assertions": [], - "variant_aliases": [], - "hgvs_expressions": [], - "clinvar_entries": [], - "allele_registry_id": null -} \ No newline at end of file diff --git a/analysis/civic/examples/harvester/v600e.json b/analysis/civic/examples/harvester/v600e.json deleted file mode 100644 index 76c32b02..00000000 --- a/analysis/civic/examples/harvester/v600e.json +++ /dev/null @@ -1,343 +0,0 @@ -{ - "id": 12, - "entrez_name": "BRAF", - "entrez_id": 673, - "name": "V600E", - "description": "BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment.", - "gene_id": 5, - "type": "variant", - "variant_types": [ - { - "id": 47, - "name": "missense_variant", - "display_name": "Missense Variant", - "so_id": "SO:0001583", - "description": "A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.", - "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0001583" - } - ], - "civic_actionability_score": 1243.5, - "coordinates": { - "chromosome": "7", - "start": 140453136, - "stop": 140453136, - "reference_bases": "A", - "variant_bases": "T", - "representative_transcript": "ENST00000288602.6", - "chromosome2": null, - "start2": null, - "stop2": null, - "representative_transcript2": null, - "ensembl_version": 75, - "reference_build": "GRCh37" - }, - "evidence_items": { - "id": 106, - "name": "EID106", - "description": "BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases.", - "disease": { - "id": 156, - "name": "Thyroid Gland Papillary Carcinoma", - "display_name": "Thyroid Gland Papillary Carcinoma", - "doid": "3969", - "url": "http://www.disease-ontology.org/?id=DOID:3969" - }, - "drugs": [], - "rating": 3, - "evidence_level": "B", - "evidence_type": "Prognostic", - "clinical_significance": "Poor Outcome", - "evidence_direction": "Supports", - "variant_origin": "Somatic", - "drug_interaction_type": null, - "status": "accepted", - "type": "evidence", - "source": { - "id": 112, - "name": "Prognostic value of the BRAF V600E mutation in papillary thyroid carcinoma.", - "citation": "He et al., 2014, Oncol Lett", - "citation_id": "24396464", - "source_type": "PubMed", - "asco_abstract_id": null, - "source_url": "http://www.ncbi.nlm.nih.gov/pubmed/24396464", - "open_access": true, - "pmc_id": "PMC3881916", - "publication_date": { - "year": 2014, - "month": 2 - }, - "journal": "Oncol Lett", - "full_journal_title": "Oncology letters", - "status": "fully curated", - "is_review": false, - "clinical_trials": [] - }, - "variant_id": 12, - "phenotypes": [] - }, - "variant_groups": [], - "assertions": [ - { - "id": 20, - "type": "assertion", - "name": "AID20", - "summary": "BRAF V600E indicates poor prognosis in advanced colorectal cancer", - "description": "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers. \nNCCN Guidelines state that that\nmutations in BRAF are a strong prognostic marker, and recommend BRAF genotyping of either primary or metastatic tumor tissue at diagnosis of stage IV disease.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [], - "evidence_type": "Prognostic", - "evidence_direction": "Supports", - "clinical_significance": "Poor Outcome", - "fda_regulatory_approval": false, - "status": "accepted" - }, - { - "id": 10, - "type": "assertion", - "name": "AID10", - "summary": "BRAF V600E mutant melanoma is sensitive to vemurafenib and cobimetinib combination therapy", - "description": "Vemurafenib and cobimetinib combination is an FDA approved and NCCN Category 1 first line treatment for BRAF V600E mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. NCCN guidelines recommend combination BRAF/MEK inhibitor therapy over BRAF inhibitor monotherapy in this treatment context. Vemurafenib and cobimetinib combination is recommend as Category 2A treatment in second-line or later contexts, and it is recommended to use treatment options different from those used with the patient during first-line therapy. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib).", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 4, - "name": "Vemurafenib", - "ncit_id": "C64768", - "aliases": [ - "Zelboraf", - "RO 5185426", - "RG7204", - "RG 7204", - "PLX4032", - "PLX-4032", - "BRAF(V600E) Kinase Inhibitor RO5185426", - "BRAF (V600E) Kinase Inhibitor RO5185426", - "1-propanesulfonamide, N-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-" - ] - }, - { - "id": 342, - "name": "Cobimetinib", - "ncit_id": "C68923", - "aliases": [ - "XL518", - "MEK Inhibitor GDC-0973", - "GDC-0973", - "Cotellic" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 12, - "type": "assertion", - "name": "AID12", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "rejected" - }, - { - "id": 7, - "type": "assertion", - "name": "AID7", - "summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", - "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved and NCCN guidelines recommend these treatments as category 1 based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Dabrafenib and trametinib are recommend as NCCN Category 2A for second line therapy in metastatic melanoma due to lack of clear Phase III trial data for this use case. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy than with BRAF inhibitor alone.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 7, - "name": "Melanoma", - "display_name": "Melanoma", - "doid": "1909", - "url": "http://www.disease-ontology.org/?id=DOID:1909" - }, - "drugs": [ - { - "id": 19, - "name": "Trametinib", - "ncit_id": "C77908", - "aliases": [ - "N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide", - "Mekinist", - "MEK Inhibitor GSK1120212", - "JTP-74057", - "GSK1120212" - ] - }, - { - "id": 22, - "name": "Dabrafenib", - "ncit_id": "C82386", - "aliases": [ - "GSK2118436", - "GSK-2118436A", - "GSK-2118436", - "BRAF Inhibitor GSK2118436", - "Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": true, - "status": "accepted" - }, - { - "id": 23, - "type": "assertion", - "name": "AID23", - "summary": "BRAFi + MEKi + EGFRi combination is recommended for BRAF V600E mutation positive colorectal cancer", - "description": "Encorafenib + binimetinib + (Cetuximab or Panitumumab) or Dabrafenib + Trametinib + (Cetuximab or Panitumumab) are recommended as subsequent therapy for BRAF V600E mutation positive colorectal cancer.", - "gene": { - "name": "BRAF", - "id": 5 - }, - "variant": { - "name": "V600E", - "id": 12 - }, - "disease": { - "id": 11, - "name": "Colorectal Cancer", - "display_name": "Colorectal Cancer", - "doid": "9256", - "url": "http://www.disease-ontology.org/?id=DOID:9256" - }, - "drugs": [ - { - "id": 16, - "name": "Cetuximab", - "ncit_id": "C1723", - "aliases": [] - }, - { - "id": 483, - "name": "Encorafenib", - "ncit_id": "C98283", - "aliases": [ - "LGX818", - "LGX-818", - "LGX 818", - "Braftovi" - ] - }, - { - "id": 485, - "name": "Binimetinib", - "ncit_id": "C84865", - "aliases": [ - "Mektovi", - "MEK162", - "ARRY-438162", - "ARRY-162" - ] - } - ], - "evidence_type": "Predictive", - "evidence_direction": "Supports", - "clinical_significance": "Sensitivity/Response", - "fda_regulatory_approval": false, - "status": "submitted" - } - ], - "variant_aliases": [ - "RS113488022", - "VAL600GLU" - ], - "hgvs_expressions": [ - "NM_004333.4:c.1799T>A", - "NP_004324.2:p.Val600Glu", - "NC_000007.13:g.140453136A>T", - "ENST00000288602.6:c.1799T>A" - ], - "clinvar_entries": [ - "13961", - "376069" - ], - "allele_registry_id": "CA123643" -} \ No newline at end of file diff --git a/analysis/civic/examples/transform/civic_cdm_example.json b/analysis/civic/examples/transform/civic_cdm_example.json deleted file mode 100644 index b00f4d1f..00000000 --- a/analysis/civic/examples/transform/civic_cdm_example.json +++ /dev/null @@ -1,361 +0,0 @@ -{ - "statements": [ - { - "id": "civic.eid:879", - "description": "A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001).", - "direction": "supports", - "evidence_level": "civic.evidence_level:B", - "proposition": "proposition:nefbQvxqptMo6fBTdwsYsJpDkSSQeTGj", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:30", - "method": "method:1", - "supported_by": [ - "pmid:23816960" - ], - "type": "Statement" - }, - { - "id": "civic.eid:883", - "description": "In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations.", - "direction": "supports", - "evidence_level": "civic.evidence_level:B", - "proposition": "proposition:nefbQvxqptMo6fBTdwsYsJpDkSSQeTGj", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:30", - "method": "method:1", - "supported_by": [ - "pmid:22452895" - ], - "type": "Statement" - }, - { - "id": "civic.eid:968", - "description": "Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay.", - "direction": "supports", - "evidence_level": "civic.evidence_level:D", - "proposition": "proposition:Zfp_VG0uvxwteCcJYO6_AJv1KDmJlFjs", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:8", - "method": "method:1", - "supported_by": [ - "pmid:26515464" - ], - "type": "Statement" - }, - { - "id": "civic.eid:982", - "description": "Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon.", - "direction": "supports", - "evidence_level": "civic.evidence_level:B", - "proposition": "proposition:nefbQvxqptMo6fBTdwsYsJpDkSSQeTGj", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:30", - "method": "method:1", - "supported_by": [ - "pmid:24439929" - ], - "type": "Statement" - }, - { - "id": "civic.eid:2629", - "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to afatinib (IC50: 0.7nM vs. 60nM) compared to wildtype EGFR cells.", - "direction": "supports", - "evidence_level": "civic.evidence_level:D", - "proposition": "proposition:Zfp_VG0uvxwteCcJYO6_AJv1KDmJlFjs", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:8", - "method": "method:1", - "supported_by": [ - "pmid:18408761" - ], - "type": "Statement" - }, - { - "id": "civic.eid:2997", - "description": "Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test", - "direction": "supports", - "evidence_level": "civic.evidence_level:A", - "proposition": "proposition:Zfp_VG0uvxwteCcJYO6_AJv1KDmJlFjs", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:8", - "method": "method:1", - "supported_by": [ - "pmid:23982599" - ], - "type": "Statement" - }, - { - "id": "civic.aid:6", - "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis, including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor afatinib is FDA approved, and is recommended (category 1) by NCCN guidelines along with erlotinib, gefitinib and osimertinib as first line systemic therapy in NSCLC with sensitizing EGFR mutation.", - "direction": "supports", - "evidence_level": "amp_asco_cap_2017_level:1A", - "proposition": "proposition:Zfp_VG0uvxwteCcJYO6_AJv1KDmJlFjs", - "variation_origin": "somatic", - "variation_descriptor": "civic.vid:33", - "therapy_descriptor": "civic.tid:146", - "disease_descriptor": "civic.did:8", - "method": "method:2", - "supported_by": [ - "document:9WsQBGXOmTFRXBUanTaIec8Gvgg8bsMA", - "civic.eid:2997", - "civic.eid:2629", - "civic.eid:982", - "civic.eid:968", - "civic.eid:883", - "civic.eid:879" - ], - "type": "Statement" - } - ], - "propositions": [ - { - "id": "proposition:nefbQvxqptMo6fBTdwsYsJpDkSSQeTGj", - "type": "therapeutic_response_proposition", - "predicate": "predicts_sensitivity_to", - "subject": "ga4gh:VA.kgjrhgf84CEndyLjKdAO0RxN-e3pJjxA", - "object_qualifier": "ncit:C3512", - "object": "rxcui:1430438" - }, - { - "id": "proposition:Zfp_VG0uvxwteCcJYO6_AJv1KDmJlFjs", - "type": "therapeutic_response_proposition", - "predicate": "predicts_sensitivity_to", - "subject": "ga4gh:VA.kgjrhgf84CEndyLjKdAO0RxN-e3pJjxA", - "object_qualifier": "ncit:C2926", - "object": "rxcui:1430438" - } - ], - "variation_descriptors": [ - { - "id": "civic.vid:33", - "type": "VariationDescriptor", - "label": "L858R", - "description": "EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies.", - "xrefs": [ - "clinvar:376280", - "clinvar:16609", - "clinvar:376282", - "caid:CA126713", - "dbsnp:121434568" - ], - "alternate_labels": [ - "LEU858ARG" - ], - "extensions": [ - { - "type": "Extension", - "name": "civic_representative_coordinate", - "value": { - "chromosome": "7", - "start": 55259515, - "stop": 55259515, - "reference_bases": "T", - "variant_bases": "G", - "representative_transcript": "ENST00000275493.2", - "ensembl_version": 75, - "reference_build": "GRCh37" - } - }, - { - "type": "Extension", - "name": "civic_actionability_score", - "value": 375 - } - ], - "variation_id": "ga4gh:VA.kgjrhgf84CEndyLjKdAO0RxN-e3pJjxA", - "variation": { - "_id": "ga4gh:VA.kgjrhgf84CEndyLjKdAO0RxN-e3pJjxA", - "type": "Allele", - "location": { - "_id": "ga4gh:VSL.Sfs_3PlVEYp9BxBsHsFfU1tvhfDq361f", - "type": "SequenceLocation", - "sequence_id": "ga4gh:SQ.vyo55F6mA6n2LgN4cagcdRzOuh38V4mE", - "interval": { - "type": "SequenceInterval", - "start": { - "type": "Number", - "value": 857 - }, - "end": { - "type": "Number", - "value": 858 - } - } - }, - "state": { - "type": "LiteralSequenceExpression", - "sequence": "R" - } - }, - "structural_type": "SO:0001583", - "expressions": [ - { - "type": "Expression", - "syntax": "hgvs:genomic", - "value": "NC_000007.13:g.55259515T>G" - }, - { - "type": "Expression", - "syntax": "hgvs:transcript", - "value": "NM_005228.4:c.2573T>G" - }, - { - "type": "Expression", - "syntax": "hgvs:transcript", - "value": "ENST00000275493.2:c.2573T>G" - }, - { - "type": "Expression", - "syntax": "hgvs:protein", - "value": "NP_005219.2:p.Leu858Arg" - } - ], - "gene_context": "civic.gid:19" - } - ], - "gene_descriptors": [ - { - "id": "civic.gid:19", - "type": "GeneDescriptor", - "label": "EGFR", - "description": "EGFR is widely recognized for its importance in cancer. Amplification and mutations have been shown to be driving events in many cancer types. Its role in non-small cell lung cancer, glioblastoma and basal-like breast cancers has spurred many research and drug development efforts. Tyrosine kinase inhibitors have shown efficacy in EGFR amplfied tumors, most notably gefitinib and erlotinib. Mutations in EGFR have been shown to confer resistance to these drugs, particularly the variant T790M, which has been functionally characterized as a resistance marker for both of these drugs. The later generation TKI's have seen some success in treating these resistant cases, and targeted sequencing of the EGFR locus has become a common practice in treatment of non-small cell lung cancer. \nOverproduction of ligands is another possible mechanism of activation of EGFR. ERBB ligands include EGF, TGF-a, AREG, EPG, BTC, HB-EGF, EPR and NRG1-4 (for detailed information please refer to the respective ligand section).", - "xrefs": [ - "ncbigene:1956" - ], - "alternate_labels": [ - "ERRP", - "EGFR", - "mENA", - "PIG61", - "NISBD2", - "HER1", - "ERBB1", - "ERBB" - ], - "gene_id": "hgnc:3236" - } - ], - "therapy_descriptors": [ - { - "id": "civic.tid:146", - "type": "TherapyDescriptor", - "label": "Afatinib", - "xrefs": [ - "ncit:C66940" - ], - "alternate_labels": [ - "BIBW2992", - "BIBW 2992", - "(2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide" - ], - "therapy_id": "rxcui:1430438" - } - ], - "disease_descriptors": [ - { - "id": "civic.did:8", - "type": "DiseaseDescriptor", - "label": "Lung Non-small Cell Carcinoma", - "xrefs": [ - "DOID:3908" - ], - "disease_id": "ncit:C2926" - }, - { - "id": "civic.did:30", - "type": "DiseaseDescriptor", - "label": "Lung Adenocarcinoma", - "xrefs": [ - "DOID:3910" - ], - "disease_id": "ncit:C3512" - } - ], - "methods": [ - { - "id": "method:1", - "label": "Standard operating procedure for curation and clinical interpretation of variants in cancer", - "url": "https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-019-0687-x", - "version": { - "year": 2019, - "month": 11, - "day": 29 - }, - "authors": "Danos, A.M., Krysiak, K., Barnell, E.K. et al.", - "type": "Method" - }, - { - "id": "method:2", - "label": "Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists", - "url": "https://pubmed.ncbi.nlm.nih.gov/27993330/", - "version": { - "year": 2017, - "month": 1 - }, - "authors": "Li MM, Datto M, Duncavage EJ, et al.", - "type": "Method" - } - ], - "documents": [ - { - "id": "pmid:23816960", - "label": "Sequist et al., 2013, J. Clin. Oncol.", - "description": "Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.", - "type": "Document" - }, - { - "id": "pmid:22452895", - "label": "Yang et al., 2012, Lancet Oncol.", - "description": "Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.", - "type": "Document" - }, - { - "id": "pmid:26515464", - "label": "Hirano et al., 2015, Oncotarget", - "description": "In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.", - "xrefs": [ - "pmc:PMC4770737" - ], - "type": "Document" - }, - { - "id": "pmid:24439929", - "label": "Wu et al., 2014, Lancet Oncol.", - "description": "Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.", - "type": "Document" - }, - { - "id": "pmid:18408761", - "label": "Li et al., 2008, Oncogene", - "description": "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.", - "xrefs": [ - "pmc:PMC2748240" - ], - "type": "Document" - }, - { - "id": "pmid:23982599", - "label": "Dungo et al., 2013, Drugs", - "description": "Afatinib: first global approval.", - "type": "Document" - }, - { - "id": "document:9WsQBGXOmTFRXBUanTaIec8Gvgg8bsMA", - "document_id": "https://www.nccn.org/professionals/physician_gls/default.aspx", - "label": "NCCN Guidelines: Non-Small Cell Lung Cancer version 3.2018", - "type": "Document" - } - ] -} \ No newline at end of file diff --git a/analysis/civic/examples/transform/civic_transform_example.py b/analysis/civic/examples/transform/civic_transform_example.py deleted file mode 100644 index ca1c4c7d..00000000 --- a/analysis/civic/examples/transform/civic_transform_example.py +++ /dev/null @@ -1,98 +0,0 @@ -"""Create an example json file for CIViC Transform.""" -import json - -from metakb import PROJECT_ROOT, APP_ROOT -from metakb.transform import CivicTransform - - -def create_civic_example(civic_data): - """Create CIViC transform examples from list of evidence items.""" - ex = { - "statements": [], - "propositions": [], - "variation_descriptors": [], - "gene_descriptors": [], - "therapy_descriptors": [], - "disease_descriptors": [], - "methods": [], - "documents": [], - } - supported_by_statement_ids = set() - for s in civic_data["statements"]: - if s["id"] == "civic.aid:6": - supported_by_statement_ids = { - s for s in s["supported_by"] if s.startswith("civic.eid") - } - supported_by_statement_ids.add(s["id"]) - break - - proposition_ids = set() - vids = set() - tids = set() - dids = set() - gids = set() - methods = set() - documents = set() - for s in civic_data["statements"]: - if s["id"] in supported_by_statement_ids: - ex["statements"].append(s) - proposition_ids.add(s["proposition"]) - vids.add(s["variation_descriptor"]) - tids.add(s["therapy_descriptor"]) - dids.add(s["disease_descriptor"]) - methods.add(s["method"]) - documents.update( - {d for d in s["supported_by"] if not d.startswith("civic.eid")} - ) - - for p in civic_data["propositions"]: - if p["id"] in proposition_ids: - ex["propositions"].append(p) - - for v in civic_data["variation_descriptors"]: - if v["id"] in vids: - ex["variation_descriptors"].append(v) - gids.add(v["gene_context"]) - - for t in civic_data["therapy_descriptors"]: - if t["id"] in tids: - ex["therapy_descriptors"].append(t) - - for d in civic_data["disease_descriptors"]: - if d["id"] in dids: - ex["disease_descriptors"].append(d) - - for g in civic_data["gene_descriptors"]: - if g["id"] in gids: - ex["gene_descriptors"].append(g) - - for m in civic_data["methods"]: - if m["id"] in methods: - ex["methods"].append(m) - - for d in civic_data["documents"]: - if d["id"] in documents: - ex["documents"].append(d) - - with open( - PROJECT_ROOT - / "analysis" - / "civic" - / "examples" # noqa: W504 - / "transform" - / "civic_cdm_example.json", - "w+", - ) as f2: - json.dump(ex, f2, indent=4) - - -if __name__ == "__main__": - civic = CivicTransform() - civic.transform() - civic.create_json() - latest = sorted( - (APP_ROOT / "data" / "civic" / "transform").glob("civic_cdm_*.json") - )[-1] # noqa: E501 - with open(latest, "r") as f: - civic_data = json.load(f) - create_civic_example(civic_data) diff --git a/analysis/graph/db_helper.py b/analysis/graph/db_helper.py deleted file mode 100644 index d9ad3d53..00000000 --- a/analysis/graph/db_helper.py +++ /dev/null @@ -1,21 +0,0 @@ -"""Utility function to load/reload graph for development.""" -from metakb.database import Graph -from metakb import APP_ROOT -import json - - -g = Graph(uri="bolt://localhost:7687", credentials=("neo4j", "admin")) -g.clear() - -fpath = APP_ROOT / "data" / "civic" / "transform" / "civic_cdm.json" -with open(fpath, "r") as f: - items = json.load(f) - -count = 0 -for item in items: - if "assertion" in item.keys(): - continue - else: - g.add_transformed_data(item) - count += 1 -print(count) diff --git a/analysis/moa/README.md b/analysis/moa/README.md deleted file mode 100644 index 5a8c70bb..00000000 --- a/analysis/moa/README.md +++ /dev/null @@ -1,16 +0,0 @@ -# MOAlmanac Harvester Analysis - -## `moa_harvester_example.py` -This script would run MOAlmanac Harvester and output the example files in a JSON format. Example files can be found in `metakb/analysis/moa/examples` - -## `Getting Started` -``` -python3 moa_harvester_example.py -``` - -## `Example Files Generated` -### Assertion Examples -The first five assertion records from Molecular Oncology Almanac will be generated with their associated source of evidence, gene and variant correspondingly. - -### Variant Examples -Specific variants: BCR-ABL1 fusion, BRAF p.V600E, EGFR amplification and TP53 are generated with their variant information correspondingly. \ No newline at end of file diff --git a/analysis/moa/examples/harvester/assertion 1.json b/analysis/moa/examples/harvester/assertion 1.json deleted file mode 100644 index ce1f6d43..00000000 --- a/analysis/moa/examples/harvester/assertion 1.json +++ /dev/null @@ -1,49 +0,0 @@ -{ - "ASSERTIONS": { - "id": 1, - "context": "Chronic, accelerated, or blast phase", - "description": "The U.S. Food and Drug Administration (FDA) granted approval for bosutinib for adult patients with chronic, accelerated, or blast phase Philidelphia chromosome-positive (Ph+) CML with resistance or intolernace to prior therapy.", - "disease": { - "name": "Chronic Myelogenous Leukemia", - "oncotree_code": "CML", - "oncotree_term": "Chronic Myelogenous Leukemia" - }, - "therapy_name": "Bosutinib", - "therapy_type": "Targeted therapy", - "clinical_significance": "sensitivity", - "predictive_implication": "FDA-Approved", - "favorable_prognosis": null, - "created_on": "11/04/21", - "last_updated": "2021-09-16", - "submitted_by": "breardon@broadinstitute.org", - "validated": true, - "source_ids": 1, - "variant": { - "id": 1, - "feature_type": "rearrangement", - "gene1": "BCR", - "gene2": "ABL1", - "locus": null, - "rearrangement_type": "Fusion", - "feature": "BCR--ABL1 Fusion" - } - }, - "SOURCES": { - "id": 1, - "type": "FDA", - "doi": null, - "nct": "None", - "pmid": "None", - "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203341s020lbl.pdf", - "citation": "Pfizer Inc. Bosulif (bosutinib) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203341s020lbl.pdf. Revised May 2021. Accessed September 16, 2021." - }, - "VARIANTS": { - "id": 1, - "feature_type": "rearrangement", - "gene1": "BCR", - "gene2": "ABL1", - "locus": null, - "rearrangement_type": "Fusion", - "feature": "BCR--ABL1 Fusion" - } -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/assertion 600.json b/analysis/moa/examples/harvester/assertion 600.json deleted file mode 100644 index ae7f1c9d..00000000 --- a/analysis/moa/examples/harvester/assertion 600.json +++ /dev/null @@ -1,65 +0,0 @@ -{ - "ASSERTIONS": { - "id": 600, - "context": "Primary", - "description": "Germline homologous recombination mutations were predictive of platinum sensitivity compared with cases without homologous recombination mutations in Ovarian, Fallopian Tube, and Peritoneal Carcinomas. Mutant cases also had better overall survival than wild type.", - "disease": { - "name": "Peritoneal Mesothelioma", - "oncotree_code": "PEMESO", - "oncotree_term": "Peritoneal Mesothelioma" - }, - "therapy_name": null, - "therapy_type": null, - "clinical_significance": null, - "predictive_implication": "Inferential", - "favorable_prognosis": true, - "created_on": "11/04/21", - "last_updated": "2017-11-03", - "submitted_by": "breardon@broadinstitute.org", - "validated": true, - "source_ids": 57, - "variant": { - "id": 597, - "alternate_allele": null, - "cdna_change": null, - "chromosome": null, - "end_position": null, - "exon": null, - "feature_type": "germline_variant", - "gene": "BARD1", - "pathogenic": null, - "protein_change": null, - "reference_allele": null, - "rsid": null, - "start_position": null, - "variant_annotation": null, - "feature": "BARD1" - } - }, - "SOURCES": { - "id": 57, - "type": "Journal", - "doi": "10.1158/1078-0432.CCR-13-2287", - "nct": "None", - "pmid": 24240112, - "url": "https://doi.org/10.1158/1078-0432.CCR-13-2287", - "citation": "Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-75." - }, - "VARIANTS": { - "id": 597, - "alternate_allele": null, - "cdna_change": null, - "chromosome": null, - "end_position": null, - "exon": null, - "feature_type": "germline_variant", - "gene": "BARD1", - "pathogenic": null, - "protein_change": null, - "reference_allele": null, - "rsid": null, - "start_position": null, - "variant_annotation": null, - "feature": "BARD1" - } -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/assertion 70.json b/analysis/moa/examples/harvester/assertion 70.json deleted file mode 100644 index a5a5e77c..00000000 --- a/analysis/moa/examples/harvester/assertion 70.json +++ /dev/null @@ -1,49 +0,0 @@ -{ - "ASSERTIONS": { - "id": 70, - "context": null, - "description": "ETS fusions did not have a better response to AR suppression and PARP inhibition.", - "disease": { - "name": "Prostate Adenocarcinoma", - "oncotree_code": "PRAD", - "oncotree_term": "Prostate Adenocarcinoma" - }, - "therapy_name": "Veliparib", - "therapy_type": "Targeted therapy", - "clinical_significance": null, - "predictive_implication": "Clinical trial", - "favorable_prognosis": null, - "created_on": "11/04/21", - "last_updated": "2019-01-29", - "submitted_by": "breardon@broadinstitute.org", - "validated": true, - "source_ids": 43, - "variant": { - "id": 67, - "feature_type": "rearrangement", - "gene1": "TMPRSS2", - "gene2": "ERG", - "locus": null, - "rearrangement_type": "Fusion", - "feature": "TMPRSS2--ERG Fusion" - } - }, - "SOURCES": { - "id": 43, - "type": "Journal", - "doi": "10.1200/JCO.2017.75.7310", - "nct": "NCT01576172", - "pmid": 29261439, - "url": "https://doi.org/10.1200/JCO.2017.75.7310", - "citation": "Hussain M, Daignault-newton S, Twardowski PW, et al. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol. 2018;36(10):991-999." - }, - "VARIANTS": { - "id": 67, - "feature_type": "rearrangement", - "gene1": "TMPRSS2", - "gene2": "ERG", - "locus": null, - "rearrangement_type": "Fusion", - "feature": "TMPRSS2--ERG Fusion" - } -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/assertion 700.json b/analysis/moa/examples/harvester/assertion 700.json deleted file mode 100644 index 5a547d92..00000000 --- a/analysis/moa/examples/harvester/assertion 700.json +++ /dev/null @@ -1,47 +0,0 @@ -{ - "ASSERTIONS": { - "id": 700, - "context": "Metastatic", - "description": "Loss of function ARID1A mutations may predict sensitivity to immune checkpoint blockade, particularly PD-L1 inhibition. Anti-PD-L1 antibody reduced tumor mutational burden and prolonged survival of mice ARID1A-deficient but not ARID1A-wild-type ovarian tumors.", - "disease": { - "name": "Ovarian Cancer, Other", - "oncotree_code": "OOVC", - "oncotree_term": "Ovarian Cancer, Other" - }, - "therapy_name": "Durvalumab", - "therapy_type": "Immunotherapy", - "clinical_significance": "sensitivity", - "predictive_implication": "Preclinical", - "favorable_prognosis": null, - "created_on": "11/04/21", - "last_updated": "2019-02-04", - "submitted_by": "breardon@broadinstitute.org", - "validated": true, - "source_ids": 51, - "variant": { - "id": 700, - "cytoband": null, - "direction": "Deletion", - "feature_type": "copy_number", - "gene": "ARID1A", - "feature": "ARID1A Deletion" - } - }, - "SOURCES": { - "id": 51, - "type": "Journal", - "doi": "10.1038/s41591-018-0012-z", - "nct": "None", - "pmid": 29736026, - "url": "https://doi.org/10.1038/s41591-018-0012-z", - "citation": "Shen J, Ju Z, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24(5):556-562." - }, - "VARIANTS": { - "id": 700, - "cytoband": null, - "direction": "Deletion", - "feature_type": "copy_number", - "gene": "ARID1A", - "feature": "ARID1A Deletion" - } -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/assertion 760.json b/analysis/moa/examples/harvester/assertion 760.json deleted file mode 100644 index 78ef6c4c..00000000 --- a/analysis/moa/examples/harvester/assertion 760.json +++ /dev/null @@ -1,47 +0,0 @@ -{ - "ASSERTIONS": { - "id": 760, - "context": null, - "description": "Results from the METEOR trial (n=658) suggest that the MET expression level might not affect treatment outcomes with cabozantinib in this patient population.", - "disease": { - "name": "Renal Clear Cell Carcinoma", - "oncotree_code": "RCC", - "oncotree_term": "Renal Clear Cell Carcinoma" - }, - "therapy_name": "Cabozantinib", - "therapy_type": "Targeted therapy", - "clinical_significance": null, - "predictive_implication": "Inferential", - "favorable_prognosis": null, - "created_on": "11/04/21", - "last_updated": "2019-08-12", - "submitted_by": "breardon@broadinstitute.org", - "validated": true, - "source_ids": 228, - "variant": { - "id": 758, - "cytoband": null, - "direction": "Amplification", - "feature_type": "copy_number", - "gene": "MET", - "feature": "MET Amplification" - } - }, - "SOURCES": { - "id": 228, - "type": "Journal", - "doi": "10.1056/NEJMoa1510016", - "nct": "NCT01865747", - "pmid": 26406150, - "url": "https://doi.org/10.1056/NEJMoa1510016", - "citation": "Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1814-23." - }, - "VARIANTS": { - "id": 758, - "cytoband": null, - "direction": "Amplification", - "feature_type": "copy_number", - "gene": "MET", - "feature": "MET Amplification" - } -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/aurka amplification.json b/analysis/moa/examples/harvester/aurka amplification.json deleted file mode 100644 index a6a5395d..00000000 --- a/analysis/moa/examples/harvester/aurka amplification.json +++ /dev/null @@ -1,8 +0,0 @@ -{ - "id": 701, - "cytoband": "20q13.2", - "direction": "Amplification", - "feature_type": "copy_number", - "gene": "AURKA", - "feature": "AURKA Amplification" -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/bcr--abl1 fusion.json b/analysis/moa/examples/harvester/bcr--abl1 fusion.json deleted file mode 100644 index 07482932..00000000 --- a/analysis/moa/examples/harvester/bcr--abl1 fusion.json +++ /dev/null @@ -1,9 +0,0 @@ -{ - "id": 1, - "feature_type": "rearrangement", - "gene1": "BCR", - "gene2": "ABL1", - "locus": null, - "rearrangement_type": "Fusion", - "feature": "BCR--ABL1 Fusion" -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/bcr.json b/analysis/moa/examples/harvester/bcr.json deleted file mode 100644 index 4610ffc7..00000000 --- a/analysis/moa/examples/harvester/bcr.json +++ /dev/null @@ -1,16 +0,0 @@ -{ - "id": 147, - "alternate_allele": null, - "cdna_change": null, - "chromosome": null, - "end_position": null, - "exon": null, - "feature_type": "somatic_variant", - "gene": "BCR", - "protein_change": null, - "reference_allele": null, - "rsid": null, - "start_position": null, - "variant_annotation": null, - "feature": "BCR" -} \ No newline at end of file diff --git a/analysis/moa/examples/harvester/moa_harvester_example.py b/analysis/moa/examples/harvester/moa_harvester_example.py deleted file mode 100644 index 8ff93992..00000000 --- a/analysis/moa/examples/harvester/moa_harvester_example.py +++ /dev/null @@ -1,71 +0,0 @@ -"""Create an example json file for MOAlmanac Harvester.""" -import json - -from metakb import PROJECT_ROOT, APP_ROOT -from metakb.harvesters import MoaHarvester - - -def create_assertion_examples(data): - """Create five MOAlmanac assertion examples.""" - assertions = [] - for i in [0, 69, 599, 699, 759]: - if data["assertions"][i]["source_ids"]: - assertions.append(data["assertions"][i]) - - for assertion in assertions: - source_id = assertion["source_ids"] - for s in data["sources"]: - if s["id"] == source_id: - source = s - break - - feature_id = assertion["variant"]["id"] - for v in data["variants"]: - if v["id"] == feature_id: - variant = v - break - - with open( - f"{PROJECT_ROOT}/analysis/moa/examples/harvester/" - f"assertion {assertion['id']}.json", - "w+", - ) as f: - example = {"ASSERTIONS": assertion, "SOURCES": source, "VARIANTS": variant} - - json.dump(example, f, indent=4) - print(f"Created JSON for evidence: assertion {assertion['id']}") - f.close() - - -def create_variant_examples(data): - """Create variant examples for BRAF600E, BCR-ABL Variant, - TP53 (Nonsense), and EGFR Amplification. - """ - variants_ids = [1, 147, 551, 701] - variants = [] - for i in range(len(data["variants"])): - if data["variants"][i]["id"] in variants_ids: - variants.append(data["variants"][i]) - for variant in variants: - with open( - f"{PROJECT_ROOT}/analysis/moa/examples/harvester/" - f"{variant['feature'].lower()}.json", - "w+", - ) as f: - f.write(json.dumps(variant, indent=4)) - print(f"Created JSON for variant: {variant['feature']}") - f.close() - - -if __name__ == "__main__": - moa = MoaHarvester() - moa.harvest() - latest = sorted( - (APP_ROOT / "data" / "moa" / "harvester").glob("moa_harvester_*.json") - )[-1] # noqa: E501 - with open(latest, "r") as f: - moa_data = json.load(f) - moa_ex_dir = PROJECT_ROOT / "analysis" / "moa" / "examples" - moa_ex_dir.mkdir(exist_ok=True, parents=True) - create_assertion_examples(moa_data) - create_variant_examples(moa_data) diff --git a/analysis/moa/examples/harvester/sf3b1 p.h662r (missense).json b/analysis/moa/examples/harvester/sf3b1 p.h662r (missense).json deleted file mode 100644 index a008ca35..00000000 --- a/analysis/moa/examples/harvester/sf3b1 p.h662r (missense).json +++ /dev/null @@ -1,16 +0,0 @@ -{ - "id": 551, - "alternate_allele": "C", - "cdna_change": "c.1985A>G", - "chromosome": "2", - "end_position": "198267372.0", - "exon": "14.0", - "feature_type": "somatic_variant", - "gene": "SF3B1", - "protein_change": "p.H662R", - "reference_allele": "T", - "rsid": null, - "start_position": "198267372.0", - "variant_annotation": "Missense", - "feature": "SF3B1 p.H662R (Missense)" -} \ No newline at end of file diff --git a/analysis/moa/examples/transform/moa.assertion:188.json b/analysis/moa/examples/transform/moa.assertion:188.json deleted file mode 100644 index 9ae1bbf6..00000000 --- a/analysis/moa/examples/transform/moa.assertion:188.json +++ /dev/null @@ -1,132 +0,0 @@ -{ - "statements": [ - { - "id": "moa.assertion:188", - "description": "BRAF V600E mutations were associated with sensitivity to the BRAF inhibitor PLX-4032 in a study of 109 microdissected pancreatic ductal adenocarcinoma patients.", - "evidence_level": "moa.evidence_level:Clinical_evidence", - "proposition": "proposition:9ANCRsSADNsbWMfmqCFFpPQfFr7-Pum1", - "variation_origin": "somatic", - "variation_descriptor": "moa.variant:149", - "therapy_descriptor": "moa.normalize.therapy:Vemurafenib", - "disease_descriptor": "moa.normalize.disease:oncotree%3APAAD", - "method": "method:4", - "supported_by": [ - "pmid:25855536" - ], - "type": "Statement" - } - ], - "propositions": [ - { - "id": "proposition:9ANCRsSADNsbWMfmqCFFpPQfFr7-Pum1", - "type": "therapeutic_response_proposition", - "predicate": "predicts_sensitivity_to", - "subject": "ga4gh:VA.8JkgnqIgYqufNl-OV_hpRG_aWF9UFQCE", - "object_qualifier": "ncit:C8294", - "object": "rxcui:1147220" - } - ], - "variation_descriptors": [ - { - "id": "moa.variant:149", - "type": "VariationDescriptor", - "label": "BRAF p.V600E (Missense)", - "extensions": [ - { - "type": "Extension", - "name": "moa_representative_coordinate", - "value": { - "chromosome": "7", - "start_position": "140453136.0", - "end_position": "140453136.0", - "reference_allele": "A", - "alternate_allele": "T", - "cdna_change": "c.1799T>A", - "protein_change": "p.V600E", - "exon": "15.0" - } - }, - { - "type": "Extension", - "name": "moa_rsid", - "value": "rs113488022" - } - ], - "variation_id": "ga4gh:VA.8JkgnqIgYqufNl-OV_hpRG_aWF9UFQCE", - "variation": { - "_id": "ga4gh:VA.8JkgnqIgYqufNl-OV_hpRG_aWF9UFQCE", - "type": "Allele", - "location": { - "_id": "ga4gh:VSL.AqrQ-EkAvTrXOFn70_8i3dXF5shBBZ5i", - "type": "SequenceLocation", - "sequence_id": "ga4gh:SQ.WaAJ_cXXn9YpMNfhcq9lnzIvaB9ALawo", - "interval": { - "type": "SequenceInterval", - "start": { - "type": "Number", - "value": 639 - }, - "end": { - "type": "Number", - "value": 640 - } - } - }, - "state": { - "type": "LiteralSequenceExpression", - "sequence": "E" - } - }, - "gene_context": "moa.normalize.gene:BRAF", - "vrs_ref_allele_seq": "V" - } - ], - "gene_descriptors": [ - { - "id": "moa.normalize.gene:BRAF", - "type": "GeneDescriptor", - "label": "BRAF", - "gene_id": "hgnc:1097" - } - ], - "therapy_descriptors": [ - { - "id": "moa.normalize.therapy:Vemurafenib", - "type": "TherapyDescriptor", - "label": "Vemurafenib", - "therapy_id": "rxcui:1147220" - } - ], - "disease_descriptors": [ - { - "id": "moa.normalize.disease:oncotree%3APAAD", - "type": "DiseaseDescriptor", - "label": "Pancreatic Adenocarcinoma", - "disease_id": "ncit:C8294" - } - ], - "methods": [ - { - "id": "method:4", - "label": "Clinical interpretation of integrative molecular profiles to guide precision cancer medicine", - "url": "https://www.biorxiv.org/content/10.1101/2020.09.22.308833v1", - "version": { - "year": 2020, - "month": 9, - "day": 22 - }, - "authors": "Reardon, B., Moore, N.D., Moore, N. et al.", - "type": "Method" - } - ], - "documents": [ - { - "id": "pmid:25855536", - "label": "Witkiewicz AK, Mcmillan EA, Balaji U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.", - "xrefs": [ - "doi:10.1038/ncomms7744" - ], - "type": "Document" - } - ] -} \ No newline at end of file diff --git a/analysis/moa/examples/transform/moa.assertion:71.json b/analysis/moa/examples/transform/moa.assertion:71.json deleted file mode 100644 index 300705b3..00000000 --- a/analysis/moa/examples/transform/moa.assertion:71.json +++ /dev/null @@ -1,127 +0,0 @@ -{ - "statements": [ - { - "id": "moa.assertion:71", - "description": "T315I mutant ABL1 in p210 BCR-ABL cells resulted in retained high levels of phosphotyrosine at increasing concentrations of inhibitor STI-571, whereas wildtype appropriately received inhibition.", - "evidence_level": "moa.evidence_level:Preclinical", - "proposition": "proposition:4BRAy5ckYBfbzLHr95Xz3M9D9mJpTRxr", - "variation_origin": "somatic", - "variation_descriptor": "moa.variant:71", - "therapy_descriptor": "moa.normalize.therapy:Imatinib", - "disease_descriptor": "moa.normalize.disease:oncotree%3ACML", - "method": "method:4", - "supported_by": [ - "pmid:11423618" - ], - "type": "Statement" - } - ], - "propositions": [ - { - "id": "proposition:4BRAy5ckYBfbzLHr95Xz3M9D9mJpTRxr", - "type": "therapeutic_response_proposition", - "predicate": "predicts_resistance_to", - "subject": "ga4gh:VA.M3CbaYfwomLqvJbdK4w-W7V-zw7LdjGj", - "object_qualifier": "ncit:C3174", - "object": "rxcui:282388" - } - ], - "variation_descriptors": [ - { - "id": "moa.variant:71", - "type": "VariationDescriptor", - "label": "ABL1 p.T315I (Missense)", - "extensions": [ - { - "type": "Extension", - "name": "moa_representative_coordinate", - "value": { - "chromosome": "9", - "start_position": "133747580.0", - "end_position": "133747580.0", - "reference_allele": "C", - "alternate_allele": "T", - "cdna_change": "c.944C>T", - "protein_change": "p.T315I", - "exon": "5.0" - } - } - ], - "variation_id": "ga4gh:VA.M3CbaYfwomLqvJbdK4w-W7V-zw7LdjGj", - "variation": { - "_id": "ga4gh:VA.M3CbaYfwomLqvJbdK4w-W7V-zw7LdjGj", - "type": "Allele", - "location": { - "_id": "ga4gh:VSL.JkBiKTd3Kq-l0ZSOzCOJ1i60mh03hXb5", - "type": "SequenceLocation", - "sequence_id": "ga4gh:SQ.dmFigTG-0fY6I54swb7PoDuxCeT6O3Wg", - "interval": { - "type": "SequenceInterval", - "start": { - "type": "Number", - "value": 314 - }, - "end": { - "type": "Number", - "value": 315 - } - } - }, - "state": { - "type": "LiteralSequenceExpression", - "sequence": "I" - } - }, - "gene_context": "moa.normalize.gene:ABL1", - "vrs_ref_allele_seq": "T" - } - ], - "gene_descriptors": [ - { - "id": "moa.normalize.gene:ABL1", - "type": "GeneDescriptor", - "label": "ABL1", - "gene_id": "hgnc:76" - } - ], - "therapy_descriptors": [ - { - "id": "moa.normalize.therapy:Imatinib", - "type": "TherapyDescriptor", - "label": "Imatinib", - "therapy_id": "rxcui:282388" - } - ], - "disease_descriptors": [ - { - "id": "moa.normalize.disease:oncotree%3ACML", - "type": "DiseaseDescriptor", - "label": "Chronic Myelogenous Leukemia", - "disease_id": "ncit:C3174" - } - ], - "methods": [ - { - "id": "method:4", - "label": "Clinical interpretation of integrative molecular profiles to guide precision cancer medicine", - "url": "https://www.biorxiv.org/content/10.1101/2020.09.22.308833v1", - "version": { - "year": 2020, - "month": 9, - "day": 22 - }, - "authors": "Reardon, B., Moore, N.D., Moore, N. et al.", - "type": "Method" - } - ], - "documents": [ - { - "id": "pmid:11423618", - "label": "Gorre, Mercedes E., et al. \"Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.\" Science 293.5531 (2001): 876-880.", - "xrefs": [ - "doi:10.1126/science.1062538" - ], - "type": "Document" - } - ] -} \ No newline at end of file diff --git a/analysis/moa/examples/transform/moa_transform_example.py b/analysis/moa/examples/transform/moa_transform_example.py deleted file mode 100644 index 3ea54e02..00000000 --- a/analysis/moa/examples/transform/moa_transform_example.py +++ /dev/null @@ -1,77 +0,0 @@ -"""Create an example json file for MOA Transform.""" -import json - -from metakb import PROJECT_ROOT, APP_ROOT -from metakb.transform import MoaTransform - - -def create_moa_example(moa_data): - """Create MOA transform examples from list of evidence items.""" - assertion_id = ["moa.assertion:71", "moa.assertion:188"] - ex = {} - proposition = None - var_des = None - t_des = None - d_des = None - g_des = None - method = None - doc = None - - for asst_id in assertion_id: - for statement in moa_data["statements"]: - if statement["id"] == asst_id: - ex["statements"] = [statement] - proposition = statement["proposition"] - var_des = statement["variation_descriptor"] - t_des = statement["therapy_descriptor"] - d_des = statement["disease_descriptor"] - method = statement["method"] - doc = statement["supported_by"][0] - - for p in moa_data["propositions"]: - if p["id"] == proposition: - ex["propositions"] = [p] - - for v in moa_data["variation_descriptors"]: - if v["id"] == var_des: - ex["variation_descriptors"] = [v] - g_des = v["gene_context"] - - for g in moa_data["gene_descriptors"]: - if g["id"] == g_des: - ex["gene_descriptors"] = [g] - - for t in moa_data["therapy_descriptors"]: - if t["id"] == t_des: - ex["therapy_descriptors"] = [t] - - for d in moa_data["disease_descriptors"]: - if d["id"] == d_des: - ex["disease_descriptors"] = [d] - - for m in moa_data["methods"]: - if m["id"] == method: - ex["methods"] = [m] - - for d in moa_data["documents"]: - if d["id"] == doc: - ex["documents"] = [d] - - with open( - f"{PROJECT_ROOT}/analysis/moa/examples/transform/" - f"{ex['statements'][0]['id']}.json", - "w+", - ) as f: - json.dump(ex, f, indent=4) - - -if __name__ == "__main__": - moa = MoaTransform() - moa.transform() - moa.create_json() - latest = sorted((APP_ROOT / "data" / "moa" / "transform").glob("moa_cdm_*.json"))[ - -1 - ] # noqa: E501 - with open(latest, "r") as f: - moa_data = json.load(f) - create_moa_example(moa_data) diff --git a/cron.yaml b/cron.yaml deleted file mode 100644 index 810a712b..00000000 --- a/cron.yaml +++ /dev/null @@ -1,5 +0,0 @@ -version: 1 -cron: - - name: "task1" - url: "/scheduled" - schedule: "* * * * *" diff --git a/pyproject.toml b/pyproject.toml index 5affbe44..4abd49b1 100644 --- a/pyproject.toml +++ b/pyproject.toml @@ -76,7 +76,7 @@ branch = true [tool.ruff] src = ["src"] -exclude = ["docs/*", "analysis/*", "codebuild/*"] +exclude = ["docs/*", "codebuild/*"] [tool.ruff.lint] select = [ diff --git a/src/metakb/__init__.py b/src/metakb/__init__.py index b0a29fd5..2c2340f6 100644 --- a/src/metakb/__init__.py +++ b/src/metakb/__init__.py @@ -4,8 +4,6 @@ from pathlib import Path APP_ROOT = Path(__file__).resolve().parents[0] -PROJECT_ROOT = Path(__file__).resolve().parents[1] - LOG_FN = "/tmp/metakb.log" if "METAKB_NORM_EB_PROD" in environ else "metakb.log" # noqa: S108 logging.basicConfig( diff --git a/src/metakb/exceptions.py b/src/metakb/exceptions.py deleted file mode 100644 index 8c1d80e6..00000000 --- a/src/metakb/exceptions.py +++ /dev/null @@ -1,5 +0,0 @@ -"""Define exceptions.""" - - -class NormalizationException(Exception): # noqa: N818 - """Indicate failure to normalize term.""" diff --git a/src/metakb/transform/civic.py b/src/metakb/transform/civic.py index 41514c9d..559a41ac 100644 --- a/src/metakb/transform/civic.py +++ b/src/metakb/transform/civic.py @@ -1,7 +1,7 @@ """A module for to transform CIViC.""" import logging import re -from enum import StrEnum +from enum import Enum from pathlib import Path from typing import Dict, List, Optional, Tuple @@ -84,11 +84,12 @@ class _VariationCache(BaseModel): members: Optional[List[models.Variation]] = None -class SourcePrefix(StrEnum): +class SourcePrefix(str, Enum): """Define constraints for source prefixes.""" PUBMED = "PUBMED" - ASCO = "asco" + ASCO = "ASCO" + ASH = "ASH" class CivicTransform(Transform): @@ -282,6 +283,8 @@ def _add_variant_therapeutic_response_studies( # Add document document = self._add_eid_document(r["source"]) + if not document: + continue # Get strength direction = self._get_evidence_direction(r["evidence_direction"]) @@ -885,9 +888,10 @@ def _add_eid_document(self, source: Dict) -> Optional[Document]: :return: Document for Evidence Item if source type is supported """ source_type = source["source_type"].upper() + source_id = source["id"] if source_type in SourcePrefix.__members__: document = Document( - id=f"civic.source:{source['id']}", + id=f"civic.source:{source_id}", label=source["citation"], title=source["title"], ).model_dump(exclude_none=True) @@ -898,7 +902,11 @@ def _add_eid_document(self, source: Dict) -> Optional[Document]: if document not in self.documents: self.documents.append(document) else: - logger.debug("%s not in schemas.SourcePrefix", source_type) + logger.warning( + "Document, %s, not supported. %s not in SourcePrefix", + source_id, + source_type, + ) document = None return document diff --git a/tests/conftest.py b/tests/conftest.py index 419f76cd..ed1b4b52 100644 --- a/tests/conftest.py +++ b/tests/conftest.py @@ -8,6 +8,8 @@ from metakb.normalizers import ViccNormalizers TEST_DATA_DIR = Path(__file__).resolve().parents[0] / "data" +TEST_HARVESTERS_DIR = TEST_DATA_DIR / "harvesters" +TEST_TRANSFORM_DIR = TEST_DATA_DIR / "transform" @pytest.fixture(scope="session") diff --git a/tests/unit/database/test_database.py b/tests/unit/database/test_database.py index c646346a..bcc2054d 100644 --- a/tests/unit/database/test_database.py +++ b/tests/unit/database/test_database.py @@ -207,7 +207,7 @@ def test_gene_rules( """Verify property and relationship rules for Gene nodes.""" check_unique_property("Gene", "id") check_relation_count( - "Gene", "Study", "HAS_GENE_CONTEXT", direction="in", min=1, max=None + "Gene", "Study", "HAS_GENE_CONTEXT", direction="in", min_rels=1, max_rels=None ) expected_labels = [{"Gene"}] @@ -244,15 +244,15 @@ def test_variation_rules( "CategoricalVariation", "HAS_DEFINING_CONTEXT", direction="in", - min=0, - max=None, + min_rels=0, + max_rels=None, ) check_relation_count( "Variation", "CategoricalVariation", "HAS_MEMBERS", - min=0, - max=None, + min_rels=0, + max_rels=None, direction="in", ) @@ -315,10 +315,10 @@ def test_categorical_variation_rules( """Verify property and relationship rules for Categorical Variation nodes.""" check_unique_property("CategoricalVariation", "id") check_relation_count( - "CategoricalVariation", "Variation", "HAS_DEFINING_CONTEXT", max=1 + "CategoricalVariation", "Variation", "HAS_DEFINING_CONTEXT", max_rels=1 ) check_relation_count( - "CategoricalVariation", "Variation", "HAS_MEMBERS", min=0, max=None + "CategoricalVariation", "Variation", "HAS_MEMBERS", min_rels=0, max_rels=None ) expected_node_labels = [{"CategoricalVariation", "ProteinSequenceConsequence"}] @@ -369,7 +369,7 @@ def test_location_rules( """Verify property and relationship rules for Location nodes.""" check_unique_property("Location", "id") check_relation_count( - "Location", "Variation", "HAS_LOCATION", direction="in", max=None + "Location", "Variation", "HAS_LOCATION", direction="in", max_rels=None ) expected_labels = [{"Location", "SequenceLocation"}] @@ -409,30 +409,33 @@ def test_therapeutic_procedure_rules( ): """Verify property and relationship rules for Therapeutic Procedure nodes.""" check_unique_property("TherapeuticProcedure", "id") - # min is 0 because TherapeuticAgent may not be attached to study directly, but + # min_rels is 0 because TherapeuticAgent may not be attached to study directly, but # through CombinationTherapy and TherapeuticSubstituteGroup check_relation_count( "TherapeuticProcedure", "Study", "HAS_THERAPEUTIC", - min=0, - max=None, + min_rels=0, + max_rels=None, direction="in", ) check_relation_count( - "CombinationTherapy", "TherapeuticAgent", "HAS_COMPONENTS", max=None + "CombinationTherapy", "TherapeuticAgent", "HAS_COMPONENTS", max_rels=None ) check_relation_count( - "CombinationTherapy", "Study", "HAS_THERAPEUTIC", max=None, direction="in" + "CombinationTherapy", "Study", "HAS_THERAPEUTIC", max_rels=None, direction="in" ) check_relation_count( - "TherapeuticSubstituteGroup", "TherapeuticAgent", "HAS_SUBSTITUTES", max=None + "TherapeuticSubstituteGroup", + "TherapeuticAgent", + "HAS_SUBSTITUTES", + max_rels=None, ) check_relation_count( "TherapeuticSubstituteGroup", "Study", "HAS_THERAPEUTIC", - max=None, + max_rels=None, direction="in", ) @@ -485,7 +488,7 @@ def test_condition_rules( """Verify property and relationship rules for condition nodes.""" check_unique_property("Condition", "id") check_relation_count( - "Condition", "Study", "HAS_TUMOR_TYPE", max=None, direction="in" + "Condition", "Study", "HAS_TUMOR_TYPE", max_rels=None, direction="in" ) expected_node_labels = [{"Disease", "Condition"}] @@ -514,8 +517,8 @@ def test_study_rules( check_relation_count("Study", "Condition", "HAS_TUMOR_TYPE") check_relation_count("Study", "TherapeuticProcedure", "HAS_THERAPEUTIC") check_relation_count("Study", "Coding", "HAS_STRENGTH") - check_relation_count("Study", "Method", "IS_SPECIFIED_BY", max=None) - check_relation_count("Study", "Gene", "HAS_GENE_CONTEXT", max=None) + check_relation_count("Study", "Method", "IS_SPECIFIED_BY", max_rels=None) + check_relation_count("Study", "Gene", "HAS_GENE_CONTEXT", max_rels=None) expected_node_labels = [{"Study", "VariantTherapeuticResponseStudy"}] check_node_labels("Study", expected_node_labels, 1) @@ -560,7 +563,7 @@ def test_document_rules( """Verify property and relationship rules for Document nodes.""" check_unique_property("Document", "id") check_relation_count( - "Document", "Study", "IS_REPORTED_IN", min=0, max=None, direction="in" + "Document", "Study", "IS_REPORTED_IN", min_rels=0, max_rels=None, direction="in" ) expected_labels = [{"Document"}] @@ -604,7 +607,9 @@ def test_method_rules( ): """Verify property and relationship rules for Method nodes.""" check_unique_property("Method", "id") - check_relation_count("Method", "Study", "IS_SPECIFIED_BY", max=None, direction="in") + check_relation_count( + "Method", "Study", "IS_SPECIFIED_BY", max_rels=None, direction="in" + ) expected_node_labels = [{"Method"}] check_node_labels("Method", expected_node_labels, 1) diff --git a/tests/unit/harvesters/moa/test_moa_assertions.py b/tests/unit/harvesters/moa/test_moa_assertions.py index 88c02d9a..4ff84f98 100644 --- a/tests/unit/harvesters/moa/test_moa_assertions.py +++ b/tests/unit/harvesters/moa/test_moa_assertions.py @@ -4,9 +4,9 @@ from unittest.mock import patch import pytest +from tests.conftest import TEST_HARVESTERS_DIR -from metakb import PROJECT_ROOT -from metakb.harvesters import MoaHarvester +from metakb.harvesters.moa import MoaHarvester @pytest.fixture(scope="module") @@ -54,13 +54,12 @@ def assertion165(): @patch.object(MoaHarvester, "_get_all_assertions") def test_assertion_170(test_get_all_assertions, test_get_all_variants, assertion165): """Test moa harvester works correctly for assertions.""" - with ( - PROJECT_ROOT / "tests" / "data" / "harvesters/moa/assertions.json" - ).open() as f: + moa_harvester_test_dir = TEST_HARVESTERS_DIR / "moa" + with (moa_harvester_test_dir / "assertions.json").open() as f: data = json.load(f) test_get_all_assertions.return_value = data - with (PROJECT_ROOT / "tests" / "data" / "harvesters/moa/variants.json").open() as f: + with (moa_harvester_test_dir / "variants.json").open() as f: data = json.load(f) test_get_all_variants.return_value = data diff --git a/tests/unit/harvesters/moa/test_moa_harvest.py b/tests/unit/harvesters/moa/test_moa_harvest.py index 1520025d..e06e2a73 100644 --- a/tests/unit/harvesters/moa/test_moa_harvest.py +++ b/tests/unit/harvesters/moa/test_moa_harvest.py @@ -1,7 +1,7 @@ """Test MOAlmanac Harvester.""" from metakb import APP_ROOT -from metakb.harvesters import MoaHarvester +from metakb.harvesters.moa import MoaHarvester def test_harvest(): diff --git a/tests/unit/harvesters/moa/test_moa_source.py b/tests/unit/harvesters/moa/test_moa_source.py index e87c55ed..4dcfdf17 100644 --- a/tests/unit/harvesters/moa/test_moa_source.py +++ b/tests/unit/harvesters/moa/test_moa_source.py @@ -3,9 +3,9 @@ from unittest.mock import patch import pytest +from tests.conftest import TEST_HARVESTERS_DIR -from metakb import PROJECT_ROOT -from metakb.harvesters import MoaHarvester +from metakb.harvesters.moa import MoaHarvester @pytest.fixture(scope="module") @@ -33,9 +33,7 @@ def source68(): @patch.object(MoaHarvester, "_get_all_assertions") def test_source68(test_get_all_assertions, source68): """Test moa harvester works correctly for evidence.""" - with ( - PROJECT_ROOT / "tests" / "data" / "harvesters/moa/assertions.json" - ).open() as f: + with (TEST_HARVESTERS_DIR / "moa" / "assertions.json").open() as f: data = json.load(f) test_get_all_assertions.return_value = data diff --git a/tests/unit/harvesters/test_civic_harvester.py b/tests/unit/harvesters/test_civic_harvester.py index 2b5300ed..23d7dde8 100644 --- a/tests/unit/harvesters/test_civic_harvester.py +++ b/tests/unit/harvesters/test_civic_harvester.py @@ -2,11 +2,12 @@ import json import pytest +from tests.conftest import TEST_HARVESTERS_DIR -from metakb import APP_ROOT, PROJECT_ROOT -from metakb.harvesters import CivicHarvester +from metakb import APP_ROOT +from metakb.harvesters.civic import CivicHarvester -TEST_DATA_PATH = PROJECT_ROOT / "tests" / "data" / "harvesters" / "civic" +TEST_DATA_PATH = TEST_HARVESTERS_DIR / "civic" TEST_CIVICPY_CACHE_PATH = sorted(TEST_DATA_PATH.glob("civicpy_cache_*.pkl"))[-1] diff --git a/tests/unit/transform/test_civic_transform_diagnostic.py b/tests/unit/transform/test_civic_transform_diagnostic.py index a89ff8af..54f69aeb 100644 --- a/tests/unit/transform/test_civic_transform_diagnostic.py +++ b/tests/unit/transform/test_civic_transform_diagnostic.py @@ -3,11 +3,11 @@ import pytest import pytest_asyncio +from tests.conftest import TEST_TRANSFORM_DIR -from metakb import PROJECT_ROOT from metakb.transform.civic import CivicTransform -DATA_DIR = PROJECT_ROOT / "tests" / "data" / "transform" / "diagnostic" +DATA_DIR = TEST_TRANSFORM_DIR / "diagnostic" FILENAME = "civic_cdm.json" diff --git a/tests/unit/transform/test_civic_transform_prognostic.py b/tests/unit/transform/test_civic_transform_prognostic.py index 75e41261..a4cb02ce 100644 --- a/tests/unit/transform/test_civic_transform_prognostic.py +++ b/tests/unit/transform/test_civic_transform_prognostic.py @@ -3,11 +3,11 @@ import pytest import pytest_asyncio +from tests.conftest import TEST_TRANSFORM_DIR -from metakb import PROJECT_ROOT from metakb.transform.civic import CivicTransform -DATA_DIR = PROJECT_ROOT / "tests" / "data" / "transform" / "prognostic" +DATA_DIR = TEST_TRANSFORM_DIR / "prognostic" FILENAME = "civic_cdm.json" diff --git a/tests/unit/transform/test_civic_transform_therapeutic.py b/tests/unit/transform/test_civic_transform_therapeutic.py index d1f99cd5..6be49bd9 100644 --- a/tests/unit/transform/test_civic_transform_therapeutic.py +++ b/tests/unit/transform/test_civic_transform_therapeutic.py @@ -3,11 +3,11 @@ import pytest import pytest_asyncio +from tests.conftest import TEST_TRANSFORM_DIR -from metakb import PROJECT_ROOT from metakb.transform.civic import CivicTransform -DATA_DIR = PROJECT_ROOT / "tests" / "data" / "transform" / "therapeutic" +DATA_DIR = TEST_TRANSFORM_DIR / "therapeutic" FILENAME = "civic_cdm.json" diff --git a/tests/unit/transform/test_moa_transform.py b/tests/unit/transform/test_moa_transform.py index 8856e57e..b29f79b7 100644 --- a/tests/unit/transform/test_moa_transform.py +++ b/tests/unit/transform/test_moa_transform.py @@ -3,11 +3,10 @@ import pytest import pytest_asyncio -from tests.conftest import TEST_DATA_DIR +from tests.conftest import TEST_TRANSFORM_DIR from metakb.transform.moa import MoaTransform -DATA_DIR = TEST_DATA_DIR / "transform" FILENAME = "moa_cdm.json" @@ -15,13 +14,15 @@ @pytest.mark.asyncio() async def data(normalizers): """Create a MOA Transform test fixture.""" - harvester_path = DATA_DIR / "moa_harvester.json" + harvester_path = TEST_TRANSFORM_DIR / "moa_harvester.json" moa = MoaTransform( - data_dir=DATA_DIR, harvester_path=harvester_path, normalizers=normalizers + data_dir=TEST_TRANSFORM_DIR, + harvester_path=harvester_path, + normalizers=normalizers, ) await moa.transform() - moa.create_json(transform_dir=DATA_DIR, filename=FILENAME) - with (DATA_DIR / FILENAME).open() as f: + moa.create_json(transform_dir=TEST_TRANSFORM_DIR, filename=FILENAME) + with (TEST_TRANSFORM_DIR / FILENAME).open() as f: return json.load(f) @@ -200,4 +201,4 @@ def studies(moa_aid66_study, moa_aid155_study): def test_moa_cdm(data, studies, check_transformed_cdm): """Test that moa transform works correctly.""" - check_transformed_cdm(data, studies, DATA_DIR / FILENAME) + check_transformed_cdm(data, studies, TEST_TRANSFORM_DIR / FILENAME)