{ "cells": [ { "cell_type": "markdown", "metadata": { "collapsed": true }, "source": [ "# Annotate Putative Somatic Variants with CIViC and VEP" ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "Welcome back to OpenCAP Jupyter Notebooks! Here you can run pre-designed code to generate an output report for your variants. \n", "\n", "To run Jupyter notebook cells hold-down on \"shift\" and select \"enter\"." ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "## Commands to annotate variants" ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "We have created a python script called identified_variants_to_annotation.py that will take in variants from the sequencing pipeline and output a document with annotation information. The output will include variant effect predictions and clinical interpretations of variants in cancer.\n", "\n", "Before running this cell, please upload your somatic variants to the home directory (see ReadTheDocs) and change the input variant list name to match your somatic variant list. You can run the cell by holding the \"shift\" key and selecting \"enter\"." ] }, { "cell_type": "code", "execution_count": null, "metadata": { "collapsed": true }, "outputs": [], "source": [ "#run command python code #input variant list\n", "%run -i 'identified_variants_to_annotation.py' 'test_annotate_variants.tsv' 'Sample_name'" ] }, { "cell_type": "code", "execution_count": 6, "metadata": { "collapsed": true }, "outputs": [], "source": [] }, { "cell_type": "code", "execution_count": 50, "metadata": { "collapsed": true }, "outputs": [], "source": [ "from docx import Document\n", "from docx.shared import Inches\n", "import pandas as pd\n", "import datetime\n", "import solvebio\n", "import myvariant\n", "import utils" ] }, { "cell_type": "code", "execution_count": 64, "metadata": { "collapsed": true }, "outputs": [], "source": [ "# Pull in variant file\n", "somatic_variants = pd.read_csv('test_annotate_variants.tsv', sep='\\t')\n", "sample_name = 'SCLC_5'" ] }, { "cell_type": "code", "execution_count": 83, "metadata": {}, "outputs": [ { "data": { "text/plain": [ "{'_license': 'http://bit.ly/2FqS871',\n", " 'allele_registry_id': 'CA123643',\n", " 'assertions': [{'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': '1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'},\n", " {'id': 342, 'name': 'Cobimetinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_item_count': 3,\n", " 'evidence_type': 'Predictive',\n", " 'fda_regulatory_approval': True,\n", " 'gene': {'id': 5, 'name': 'BRAF'},\n", " 'id': 10,\n", " 'name': 'AID10',\n", " 'open_change_count': 0,\n", " 'pending_evidence_count': 0,\n", " 'status': 'accepted',\n", " 'summary': 'BRAF V600E mutant melanoma is sensitive to vemurafenib and cobimetinib combination therapy',\n", " 'type': 'assertion',\n", " 'variant': {'id': 12, 'name': 'V600E'}},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': '1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_item_count': 8,\n", " 'evidence_type': 'Predictive',\n", " 'fda_regulatory_approval': True,\n", " 'gene': {'id': 5, 'name': 'BRAF'},\n", " 'id': 12,\n", " 'name': 'AID12',\n", " 'open_change_count': 0,\n", " 'pending_evidence_count': 0,\n", " 'status': 'rejected',\n", " 'summary': 'BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy',\n", " 'type': 'assertion',\n", " 'variant': {'id': 12, 'name': 'V600E'}},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': '1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_item_count': 4,\n", " 'evidence_type': 'Predictive',\n", " 'fda_regulatory_approval': True,\n", " 'gene': {'id': 5, 'name': 'BRAF'},\n", " 'id': 7,\n", " 'name': 'AID7',\n", " 'open_change_count': 0,\n", " 'pending_evidence_count': 0,\n", " 'status': 'accepted',\n", " 'summary': 'BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy',\n", " 'type': 'assertion',\n", " 'variant': {'id': 12, 'name': 'V600E'}},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': '9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_item_count': 6,\n", " 'evidence_type': 'Prognostic',\n", " 'fda_regulatory_approval': False,\n", " 'gene': {'id': 5, 'name': 'BRAF'},\n", " 'id': 20,\n", " 'name': 'AID20',\n", " 'open_change_count': 0,\n", " 'pending_evidence_count': 0,\n", " 'status': 'accepted',\n", " 'summary': 'BRAF V600E indicates poor prognosis in advanced colorectal cancer',\n", " 'type': 'assertion',\n", " 'variant': {'id': 12, 'name': 'V600E'}}],\n", " 'civic_actionability_score': 1019.0,\n", " 'clinvar_entries': '13961',\n", " 'coordinates': {'chromosome': '7',\n", " 'ensembl_version': 75,\n", " 'reference_bases': 'A',\n", " 'reference_build': 'GRCh37',\n", " 'representative_transcript': 'ENST00000288602.6',\n", " 'start': 140453136,\n", " 'stop': 140453136,\n", " 'variant_bases': 'T'},\n", " '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.',\n", " 'entrez_id': 673,\n", " 'entrez_name': 'BRAF',\n", " 'evidence_items': [{'clinical_significance': 'Resistance',\n", " 'description': 'In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with BRAF V600E (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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3739,\n", " 'name': 'EID3739',\n", " 'open_change_count': 1,\n", " 'source': {'citation': 'Kaczirek et al., 2015, Clin Colorectal Cancer',\n", " 'full_journal_title': 'Clinical colorectal cancer',\n", " 'id': 1920,\n", " 'is_review': False,\n", " 'journal': 'Clin Colorectal Cancer',\n", " '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.',\n", " 'publication_date': {'month': 6, 'year': 2015},\n", " 'pubmed': 25666295,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25666295',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Negative',\n", " '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).',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 1940,\n", " 'name': 'EID1940',\n", " 'open_change_count': 1,\n", " 'rating': 4,\n", " 'source': {'citation': 'Schell et al., 2016, Nat Commun',\n", " 'full_journal_title': 'Nature communications',\n", " 'id': 1367,\n", " 'is_review': False,\n", " 'journal': 'Nat Commun',\n", " 'name': 'A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4912618',\n", " 'publication_date': {'day': 15, 'month': 6, 'year': 2016},\n", " 'pubmed': 27302369,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27302369',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Two cases of patients with BRAF V600E positive cholangiocarcinoma showed excellent response for Dabrafenib and Trametinib.',\n", " 'disease': {'display_name': 'Cholangiocarcinoma',\n", " 'doid': 'DOID:4947',\n", " 'id': 29,\n", " 'name': 'Cholangiocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4947'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 548, 'name': 'Trametinib DMSO'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5903,\n", " 'name': 'EID5903',\n", " 'open_change_count': 1,\n", " 'rating': 3,\n", " 'source': {'citation': 'Lavingia et al., 2016, J Gastrointest Oncol',\n", " 'full_journal_title': 'Journal of gastrointestinal oncology',\n", " 'id': 2380,\n", " 'is_review': False,\n", " 'journal': 'J Gastrointest Oncol',\n", " 'name': 'Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5177579',\n", " 'publication_date': {'month': 12, 'year': 2016},\n", " 'pubmed': 28078132,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/28078132',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Chemotherapy-refractory, metastatic cholangiocarcinoma with BRAF V600E showed dramatically response for Dabrafenib and Trametinib combination.',\n", " 'disease': {'display_name': 'Cholangiocarcinoma',\n", " 'doid': 'DOID:4947',\n", " 'id': 29,\n", " 'name': 'Cholangiocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4947'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 548, 'name': 'Trametinib DMSO'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5902,\n", " 'name': 'EID5902',\n", " 'open_change_count': 1,\n", " 'rating': 3,\n", " 'source': {'citation': 'Kocsis et al., 2017, J Gastrointest Oncol',\n", " 'full_journal_title': 'Journal of gastrointestinal oncology',\n", " 'id': 2381,\n", " 'is_review': False,\n", " 'journal': 'J Gastrointest Oncol',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5401859',\n", " 'publication_date': {'month': 4, 'year': 2017},\n", " 'pubmed': 28480077,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/28480077',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Dabrafenib and trametinib combination showed durable response for patients with standard chemotherapy refractory cholangiocarcinoma havoring BRAF V600E.',\n", " 'disease': {'display_name': 'Cholangiocarcinoma',\n", " 'doid': 'DOID:4947',\n", " 'id': 29,\n", " 'name': 'Cholangiocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4947'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 548, 'name': 'Trametinib DMSO'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5904,\n", " 'name': 'EID5904',\n", " 'open_change_count': 1,\n", " 'rating': 3,\n", " 'source': {'citation': 'Loaiza-Bonilla et al., 2014, Ecancermedicalscience',\n", " 'full_journal_title': 'Ecancermedicalscience',\n", " 'id': 2379,\n", " 'is_review': False,\n", " 'journal': 'Ecancermedicalscience',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4239128',\n", " 'publication_date': {'year': 2014},\n", " 'pubmed': 25435907,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25435907',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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; however, 15% (25/167) of patients harboring BRAF V600E experienced progressive disease.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3757,\n", " 'name': 'EID3757',\n", " 'open_change_count': 1,\n", " 'source': {'citation': 'Ugurel et al., 2015, Ann. Oncol.',\n", " 'full_journal_title': 'Annals of oncology : official journal of the European Society for Medical Oncology',\n", " 'id': 1957,\n", " 'is_review': False,\n", " 'journal': 'Ann. Oncol.',\n", " 'name': 'A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.',\n", " 'publication_date': {'month': 3, 'year': 2015},\n", " 'pubmed': 25524477,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25524477',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Cholangiocarcinoma',\n", " 'doid': 'DOID:4947',\n", " 'id': 29,\n", " 'name': 'Cholangiocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4947'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 101, 'name': 'Irinotecan'},\n", " {'id': 28, 'name': 'Panitumumab'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5906,\n", " 'name': 'EID5906',\n", " 'open_change_count': 1,\n", " 'rating': 3,\n", " 'source': {'citation': 'Silkin et al., 2016, J Gastrointest Cancer',\n", " 'full_journal_title': 'Journal of gastrointestinal cancer',\n", " 'id': 2382,\n", " 'is_review': False,\n", " 'journal': 'J Gastrointest Cancer',\n", " 'name': 'Complete Clinical Response of BRAF-Mutated Cholangiocarcinoma to Vemurafenib, Panitumumab, and Irinotecan.',\n", " 'publication_date': {'month': 12, 'year': 2016},\n", " 'pubmed': 26687137,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26687137',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'In patients with multiple myeloma, those with BRAF V600E had shorter overall survival than wild-type.',\n", " 'disease': {'display_name': 'Myeloma',\n", " 'doid': 'DOID:0070004',\n", " 'id': 224,\n", " 'name': 'Myeloma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:0070004'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 463,\n", " 'name': 'EID463',\n", " 'open_change_count': 1,\n", " 'rating': 3,\n", " 'source': {'citation': 'Andrulis et al., 2013, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 278,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'Targeting the BRAF V600E mutation in multiple myeloma.',\n", " 'publication_date': {'month': 8, 'year': 2013},\n", " 'pubmed': 23612012,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23612012',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'In a case report, a cervicomedullary ganglioglioma patient harboring BRAF V600E mutation was associated with radiological and clinical response to vemurafenib monotherapy 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.',\n", " 'disease': {'display_name': 'Ganglioglioma',\n", " 'doid': 'DOID:5078',\n", " 'id': 2604,\n", " 'name': 'Ganglioglioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:5078'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3777,\n", " 'name': 'EID3777',\n", " 'open_change_count': 1,\n", " 'source': {'citation': 'del Bufalo et al., 2014, J Transl Med',\n", " 'full_journal_title': 'Journal of translational medicine',\n", " 'id': 1974,\n", " 'is_review': False,\n", " 'journal': 'J Transl Med',\n", " 'name': 'Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4279809',\n", " 'publication_date': {'day': 19, 'month': 12, 'year': 2014},\n", " 'pubmed': 25524464,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25524464',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Ovarian Cystadenocarcinoma',\n", " 'doid': 'DOID:3605',\n", " 'id': 816,\n", " 'name': 'Ovarian Cystadenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3605'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3787,\n", " 'name': 'EID3787',\n", " 'open_change_count': 1,\n", " 'source': {'citation': 'Combe et al., 2015, Invest New Drugs',\n", " 'full_journal_title': 'Investigational new drugs',\n", " 'id': 1984,\n", " 'is_review': False,\n", " 'journal': 'Invest New Drugs',\n", " 'name': 'Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation.',\n", " 'publication_date': {'month': 12, 'year': 2015},\n", " 'pubmed': 26490654,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26490654',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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. Patients without the V600E mutation had evidence of tumor regression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1749,\n", " 'name': 'EID1749',\n", " 'open_change_count': 1,\n", " 'rating': 4,\n", " 'source': {'citation': 'Flaherty et al., 2010, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 352,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Inhibition of mutated, activated BRAF in metastatic melanoma.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3724529',\n", " 'publication_date': {'day': 26, 'month': 8, 'year': 2010},\n", " 'pubmed': 20818844,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20818844',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'description': 'In an 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 a complete response with 61 weeks of vemurafenib monotherapy followed by disease progression.',\n", " 'disease': {'display_name': 'Thyroid Carcinoma',\n", " 'doid': 'DOID:3963',\n", " 'id': 155,\n", " 'name': 'Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3963'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3744,\n", " 'name': 'EID3744',\n", " 'open_change_count': 1,\n", " 'source': {'citation': 'Prager et al., 2016, Thyroid',\n", " 'full_journal_title': 'Thyroid : official journal of the American Thyroid Association',\n", " 'id': 1949,\n", " 'is_review': False,\n", " 'journal': 'Thyroid',\n", " 'name': 'Sustained Response to Vemurafenib in a BRAF(V600E)-Mutated Anaplastic Thyroid Carcinoma Patient.',\n", " 'publication_date': {'month': 10, 'year': 2016},\n", " 'pubmed': 27532222,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27532222',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Anaplastic Thyroid Carcinoma',\n", " 'id': 2952,\n", " 'name': 'Anaplastic Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6975,\n", " 'name': 'EID6975',\n", " 'open_change_count': 1,\n", " 'rating': 4,\n", " 'source': {'citation': 'Subbiah et al., 2018, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2686,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5791845',\n", " 'publication_date': {'day': 1, 'month': 1, 'year': 2018},\n", " 'pubmed': 29072975,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29072975',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 106,\n", " 'name': 'EID106',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'He et al., 2014, Oncol Lett',\n", " 'full_journal_title': 'Oncology letters',\n", " 'id': 112,\n", " 'is_review': False,\n", " 'journal': 'Oncol Lett',\n", " 'name': 'Prognostic value of the BRAF V600E mutation in papillary thyroid carcinoma.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3881916',\n", " 'publication_date': {'month': 2, 'year': 2014},\n", " 'pubmed': 24396464,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24396464',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 28, 'name': 'Panitumumab'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6123,\n", " 'name': 'EID6123',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Corcoran et al., 2018, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 2468,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5882509',\n", " 'publication_date': {'month': 4, 'year': 2018},\n", " 'pubmed': 29431699,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29431699',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 459, 'name': 'PD 0325901'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2125,\n", " 'name': 'EID2125',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 7156,\n", " 'name': 'EID7156',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Roth et al., 2010, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2783,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " '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.',\n", " 'publication_date': {'day': 20, 'month': 1, 'year': 2010},\n", " 'pubmed': 20008640,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20008640',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'In a study of 322 advanced melanoma patients with BRAF-V600E or BRAF-V600K mutations, treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo, <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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2135,\n", " 'name': 'EID2135',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Flaherty et al., 2012, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1210,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Improved survival with MEK inhibition in BRAF-mutated melanoma.',\n", " 'publication_date': {'day': 12, 'month': 7, 'year': 2012},\n", " 'pubmed': 22663011,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22663011',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 33, 'name': 'Bevacizumab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2121,\n", " 'name': 'EID2121',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Tol et al., 2009, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1481,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'BRAF mutation in metastatic colorectal cancer.',\n", " 'publication_date': {'day': 2, 'month': 7, 'year': 2009},\n", " 'pubmed': 19571295,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19571295',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Glioblastoma Multiforme',\n", " 'doid': 'DOID:3068',\n", " 'id': 19,\n", " 'name': 'Glioblastoma Multiforme',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3068'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3771,\n", " 'name': 'EID3771',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Robinson et al., 2014, BMC Cancer',\n", " 'full_journal_title': 'BMC cancer',\n", " 'id': 1968,\n", " 'is_review': False,\n", " 'journal': 'BMC Cancer',\n", " 'name': 'Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3996187',\n", " 'publication_date': {'day': 12, 'month': 4, 'year': 2014},\n", " 'pubmed': 24725538,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24725538',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 462, 'name': 'CI-1040'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2136,\n", " 'name': 'EID2136',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Liu et al., 2007, J. Clin. Endocrinol. Metab.',\n", " 'full_journal_title': 'The Journal of clinical endocrinology and metabolism',\n", " 'id': 1493,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Endocrinol. Metab.',\n", " '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.',\n", " 'publication_date': {'month': 12, 'year': 2007},\n", " 'pubmed': 17911174,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/17911174',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'description': 'BRAF status does not predict outcome in patients treated with dacarbazine or temozolomide.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Substitutes',\n", " 'drugs': [{'id': 11, 'name': 'Temozolomide'},\n", " {'id': 25, 'name': 'Dacarbazine'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 82,\n", " 'name': 'EID82',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Meckbach et al., 2014, PLoS ONE',\n", " 'full_journal_title': 'PloS one',\n", " 'id': 96,\n", " 'is_review': False,\n", " 'journal': 'PLoS ONE',\n", " 'name': 'BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3930670',\n", " 'publication_date': {'year': 2014},\n", " 'pubmed': 24586605,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24586605',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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�s 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.',\n", " 'disease': {'display_name': 'Lung Adenocarcinoma',\n", " 'doid': 'DOID:3910',\n", " 'id': 26,\n", " 'name': 'Lung Adenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3910'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3781,\n", " 'name': 'EID3781',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Peters et al., 2013, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 1978,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma.',\n", " 'publication_date': {'day': 10, 'month': 7, 'year': 2013},\n", " 'pubmed': 23733758,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23733758',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model has shown a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 122, 'name': 'Selumetinib (AZD6244)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2130,\n", " 'name': 'EID2130',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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).',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 2503,\n", " 'name': 'EID2503',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Kim et al., 2012, Cancer',\n", " 'full_journal_title': 'Cancer',\n", " 'id': 1495,\n", " 'is_review': False,\n", " 'journal': 'Cancer',\n", " 'name': 'The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2012},\n", " 'pubmed': 21882184,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21882184',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'},\n", " {'id': 14, 'name': 'Gefitinib'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1408,\n", " 'name': 'EID1408',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Prahallad et al., 2012, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 344,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.',\n", " 'publication_date': {'day': 1, 'month': 3, 'year': 2012},\n", " 'pubmed': 22281684,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22281684',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2132,\n", " 'name': 'EID2132',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Nazarian et al., 2010, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 1491,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3143360',\n", " 'publication_date': {'day': 16, 'month': 12, 'year': 2010},\n", " 'pubmed': 21107323,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21107323',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 28, 'name': 'Panitumumab'},\n", " {'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 89,\n", " 'name': 'EID89',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Di Nicolantonio et al., 2008, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 100,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.',\n", " 'publication_date': {'day': 10, 'month': 12, 'year': 2008},\n", " 'pubmed': 19001320,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19001320',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Substitutes',\n", " 'drugs': [{'id': 28, 'name': 'Panitumumab'},\n", " {'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 816,\n", " 'name': 'EID816',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Rowland et al., 2015, Br. J. Cancer',\n", " 'full_journal_title': 'British journal of cancer',\n", " 'id': 548,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Cancer',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4580381',\n", " 'publication_date': {'day': 9, 'month': 6, 'year': 2015},\n", " 'pubmed': 25989278,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25989278',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Skin Melanoma',\n", " 'doid': 'DOID:8923',\n", " 'id': 206,\n", " 'name': 'Skin Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:8923'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3758,\n", " 'name': 'EID3758',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Robert et al., 2015, N. Engl. J. Med.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT01597908',\n", " '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.',\n", " 'name': 'Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma',\n", " 'nct_id': 'NCT01597908'}],\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 353,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Improved overall survival in melanoma with combined dabrafenib and trametinib.',\n", " 'publication_date': {'day': 1, 'month': 1, 'year': 2015},\n", " 'pubmed': 25399551,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25399551',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Thyroid cancer cell lines with BRAF V600E mutations were more sensitive to vemurafenib than those with wildtype BRAF (IC50: 0.115� 1.156 uM vs. 56.674�1349.788 uM).',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3760,\n", " 'name': 'EID3760',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Sala et al., 2008, Mol. Cancer Res.',\n", " 'full_journal_title': 'Molecular cancer research : MCR',\n", " 'id': 1959,\n", " 'is_review': False,\n", " 'journal': 'Mol. Cancer Res.',\n", " 'name': 'BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells.',\n", " 'publication_date': {'month': 5, 'year': 2008},\n", " 'pubmed': 18458053,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18458053',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Substitutes',\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'},\n", " {'id': 28, 'name': 'Panitumumab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2115,\n", " 'name': 'EID2115',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Di Nicolantonio et al., 2008, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 100,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.',\n", " 'publication_date': {'day': 10, 'month': 12, 'year': 2008},\n", " 'pubmed': 19001320,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19001320',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 101, 'name': 'Irinotecan'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2118,\n", " 'name': 'EID2118',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Souglakos et al., 2009, Br. J. Cancer',\n", " 'full_journal_title': 'British journal of cancer',\n", " 'id': 1479,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Cancer',\n", " 'name': 'Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2720232',\n", " 'publication_date': {'day': 4, 'month': 8, 'year': 2009},\n", " 'pubmed': 19603024,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19603024',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 617, 'name': 'BMS-754807'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 7077,\n", " 'name': 'EID7077',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Huang et al., 2015, Mol. Cancer Ther.',\n", " 'full_journal_title': 'Molecular cancer therapeutics',\n", " 'id': 2752,\n", " 'is_review': False,\n", " 'journal': 'Mol. Cancer Ther.',\n", " '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.',\n", " 'publication_date': {'month': 2, 'year': 2015},\n", " 'pubmed': 25527633,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25527633',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Mouse xenografts using HT29 cells harboring the BRAF V600E mutation treated with combination therapy (capecitabine, vemurafenib, bevacizumab) showed increased survival and reduced tumor burden compared to single and double agent therapies.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 33, 'name': 'Bevacizumab'},\n", " {'id': 4, 'name': 'Vemurafenib'},\n", " {'id': 32, 'name': 'Capecitabine'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 98,\n", " 'name': 'EID98',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Yang et al., 2012, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 108,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.',\n", " 'publication_date': {'day': 1, 'month': 2, 'year': 2012},\n", " 'pubmed': 22180495,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22180495',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5960,\n", " 'name': 'EID5960',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Hainsworth et al., 2018, J. Clin. Oncol.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT02091141',\n", " '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.\",\n", " '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',\n", " 'nct_id': 'NCT02091141'}],\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2414,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.',\n", " 'publication_date': {'day': 10, 'month': 1, 'year': 2018},\n", " 'pubmed': 29320312,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29320312',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Acquired resistance to vemurafenib in BRAF-V600E positive melanomas frequently confound vemurafenib therapy.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2133,\n", " 'name': 'EID2133',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Johannessen et al., 2010, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 1492,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3058384',\n", " 'publication_date': {'day': 16, 'month': 12, 'year': 2010},\n", " 'pubmed': 21107320,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21107320',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 122, 'name': 'Selumetinib (AZD6244)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2145,\n", " 'name': 'EID2145',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Horbinski et al., 2012, Neuro-oncology',\n", " 'full_journal_title': 'Neuro-oncology',\n", " 'id': 1499,\n", " 'is_review': False,\n", " 'journal': 'Neuro-oncology',\n", " 'name': 'Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3367847',\n", " 'publication_date': {'month': 6, 'year': 2012},\n", " 'pubmed': 22492957,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22492957',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'BRAF V600E is correlated with shorter disease-free and overall Survival in a Spanish cohort of melanoma patients.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 104,\n", " 'name': 'EID104',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Nagore et al., 2014, J. Am. Acad. Dermatol.',\n", " 'full_journal_title': 'Journal of the American Academy of Dermatology',\n", " 'id': 111,\n", " 'is_review': False,\n", " 'journal': 'J. Am. Acad. Dermatol.',\n", " 'name': 'Prognostic value of BRAF mutations in localized cutaneous melanoma.',\n", " 'publication_date': {'month': 5, 'year': 2014},\n", " 'pubmed': 24388723,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24388723',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'Unlike other studies that suggest a poorer outcome, BRAF mutation in this study was not correlated with poorer prognosis in papillary thyroid cancer.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 102,\n", " 'name': 'EID102',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Walczyk et al., 2014, Clin. Endocrinol. (Oxf)',\n", " 'full_journal_title': 'Clinical endocrinology',\n", " 'id': 109,\n", " 'is_review': False,\n", " 'journal': 'Clin. Endocrinol. (Oxf)',\n", " 'name': 'The BRAF(V600E) mutation in papillary thyroid microcarcinoma: does the mutation have an impact on clinical outcome?',\n", " 'publication_date': {'month': 6, 'year': 2014},\n", " 'pubmed': 24354346,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24354346',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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�s 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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 101, 'name': 'Irinotecan'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2119,\n", " 'name': 'EID2119',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Loupakis et al., 2009, Br. J. Cancer',\n", " 'full_journal_title': 'British journal of cancer',\n", " 'id': 1480,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Cancer',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2736831',\n", " 'publication_date': {'day': 18, 'month': 8, 'year': 2009},\n", " 'pubmed': 19603018,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19603018',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3768,\n", " 'name': 'EID3768',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Follows et al., 2013, Br. J. Haematol.',\n", " 'full_journal_title': 'British journal of haematology',\n", " 'id': 1965,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Haematol.',\n", " 'name': 'Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to low dose vemurafenib.',\n", " 'publication_date': {'month': 4, 'year': 2013},\n", " 'pubmed': 23278307,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23278307',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}, {'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2894,\n", " 'name': 'EID2894',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Di Nicolantonio et al., 2008, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 100,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.',\n", " 'publication_date': {'day': 10, 'month': 12, 'year': 2008},\n", " 'pubmed': 19001320,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19001320',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 101, 'name': 'Irinotecan'},\n", " {'id': 16, 'name': 'Cetuximab'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1902,\n", " 'name': 'EID1902',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Hong et al., 2016, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 1336,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.',\n", " 'publication_date': {'month': 12, 'year': 2016},\n", " 'pubmed': 27729313,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27729313',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 344, 'name': 'GDC-0879'},\n", " {'id': 343, 'name': 'BEZ235 (NVP-BEZ235, Dactolisib)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1428,\n", " 'name': 'EID1428',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Coffee et al., 2013, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 967,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3815598',\n", " 'publication_date': {'day': 15, 'month': 5, 'year': 2013},\n", " 'pubmed': 23549875,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23549875',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'drugs': [{'id': 20, 'name': 'Dasatinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3775,\n", " 'name': 'EID3775',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Henderson et al., 2014, Head Neck',\n", " 'full_journal_title': 'Head & neck',\n", " 'id': 1972,\n", " 'is_review': False,\n", " 'journal': 'Head Neck',\n", " 'name': 'Src inhibitors in suppression of papillary thyroid carcinoma growth.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4401074',\n", " 'publication_date': {'month': 3, 'year': 2014},\n", " 'pubmed': 23729178,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23729178',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Anaplastic Thyroid Carcinoma',\n", " 'id': 2952,\n", " 'name': 'Anaplastic Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 247, 'name': 'Pertuzumab'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5961,\n", " 'name': 'EID5961',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Hainsworth et al., 2018, J. Clin. Oncol.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT02091141',\n", " '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.\",\n", " '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',\n", " 'nct_id': 'NCT02091141'}],\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2414,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.',\n", " 'publication_date': {'day': 10, 'month': 1, 'year': 2018},\n", " 'pubmed': 29320312,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29320312',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1414,\n", " 'name': 'EID1414',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Ali et al., 2014, Case Rep Oncol',\n", " 'full_journal_title': 'Case reports in oncology',\n", " 'id': 958,\n", " 'is_review': False,\n", " 'journal': 'Case Rep Oncol',\n", " 'name': 'Extended Antitumor Response of a BRAF V600E Papillary Thyroid Carcinoma to Vemurafenib.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4067722',\n", " 'publication_date': {'month': 5, 'year': 2014},\n", " 'pubmed': 24987354,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24987354',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Cancer',\n", " 'doid': 'DOID:162',\n", " 'id': 216,\n", " 'name': 'Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:162'},\n", " 'drugs': [{'id': 342, 'name': 'Cobimetinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1141,\n", " 'name': 'EID1141',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Hatzivassiliou et al., 2013, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 790,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.',\n", " 'publication_date': {'day': 12, 'month': 9, 'year': 2013},\n", " 'pubmed': 23934108,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23934108',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Multiple Myeloma',\n", " 'doid': 'DOID:9538',\n", " 'id': 41,\n", " 'name': 'Multiple Myeloma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9538'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1699,\n", " 'name': 'EID1699',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Sharman et al., 2014, Clin Lymphoma Myeloma Leuk',\n", " 'full_journal_title': 'Clinical lymphoma, myeloma & leukemia',\n", " 'id': 1147,\n", " 'is_review': False,\n", " 'journal': 'Clin Lymphoma Myeloma Leuk',\n", " 'name': 'Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma.',\n", " 'publication_date': {'month': 10, 'year': 2014},\n", " 'pubmed': 24997557,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24997557',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 463, 'name': 'RDEA 119'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2140,\n", " 'name': 'EID2140',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Kim et al., 2012, Cancer',\n", " 'full_journal_title': 'Cancer',\n", " 'id': 1495,\n", " 'is_review': False,\n", " 'journal': 'Cancer',\n", " 'name': 'The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2012},\n", " 'pubmed': 21882184,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21882184',\n", " 'status': 'partially curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " 'description': 'In a patient with V600E-positive NSCLC, KRAS G12D seemed to confer resistance to dabrafenib.',\n", " 'disease': {'display_name': 'Non-small Cell Lung Carcinoma',\n", " 'doid': 'DOID:3908',\n", " 'id': 8,\n", " 'name': 'Non-small Cell Lung Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3908'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 91,\n", " 'name': 'EID91',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Rudin et al., 2013, J Thorac Oncol',\n", " 'full_journal_title': 'Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer',\n", " 'id': 101,\n", " 'is_review': False,\n", " 'journal': 'J Thorac Oncol',\n", " 'name': 'Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3634121',\n", " 'publication_date': {'month': 5, 'year': 2013},\n", " 'pubmed': 23524406,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23524406',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 462, 'name': 'CI-1040'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2138,\n", " 'name': 'EID2138',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Kim et al., 2012, Cancer',\n", " 'full_journal_title': 'Cancer',\n", " 'id': 1495,\n", " 'is_review': False,\n", " 'journal': 'Cancer',\n", " 'name': 'The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2012},\n", " 'pubmed': 21882184,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21882184',\n", " 'status': 'partially curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Multiple Myeloma',\n", " 'doid': 'DOID:9538',\n", " 'id': 41,\n", " 'name': 'Multiple Myeloma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9538'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1698,\n", " 'name': 'EID1698',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Sharman et al., 2014, Clin Lymphoma Myeloma Leuk',\n", " 'full_journal_title': 'Clinical lymphoma, myeloma & leukemia',\n", " 'id': 1147,\n", " 'is_review': False,\n", " 'journal': 'Clin Lymphoma Myeloma Leuk',\n", " 'name': 'Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma.',\n", " 'publication_date': {'month': 10, 'year': 2014},\n", " 'pubmed': 24997557,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24997557',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 7157,\n", " 'name': 'EID7157',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Van Cutsem et al., 2011, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 1931,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " '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.',\n", " 'publication_date': {'day': 20, 'month': 5, 'year': 2011},\n", " 'pubmed': 21502544,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21502544',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3749,\n", " 'name': 'EID3749',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Rizos et al., 2014, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 1951,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2014},\n", " 'pubmed': 24463458,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24463458',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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).',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 656,\n", " 'name': 'EID656',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Xing et al., 2014, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 413,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4145183',\n", " 'publication_date': {'day': 1, 'month': 9, 'year': 2014},\n", " 'pubmed': 25024077,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25024077',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Combined MEK 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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 515, 'name': 'GDC0941'}, {'id': 30, 'name': 'PLX4720'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 96,\n", " 'name': 'EID96',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Rad et al., 2013, Cancer Cell',\n", " 'full_journal_title': 'Cancer cell',\n", " 'id': 106,\n", " 'is_review': False,\n", " 'journal': 'Cancer Cell',\n", " 'name': 'A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3706745',\n", " 'publication_date': {'day': 8, 'month': 7, 'year': 2013},\n", " 'pubmed': 23845441,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23845441',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Thyroid Carcinoma',\n", " 'doid': 'DOID:3963',\n", " 'id': 155,\n", " 'name': 'Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3963'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3784,\n", " 'name': 'EID3784',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Xing et al., 2011, Biochem. Biophys. Res. Commun.',\n", " 'full_journal_title': 'Biochemical and biophysical research communications',\n", " 'id': 1981,\n", " 'is_review': False,\n", " 'journal': 'Biochem. Biophys. Res. Commun.',\n", " 'name': 'The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204).',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4596240',\n", " 'publication_date': {'day': 28, 'month': 1, 'year': 2011},\n", " 'pubmed': 21185263,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21185263',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'V600E is correlated with disease recurrence in both age cohorts (>65 and <65 yo).',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 107,\n", " 'name': 'EID107',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Howell et al., 2011, Ann. Surg. Oncol.',\n", " 'full_journal_title': 'Annals of surgical oncology',\n", " 'id': 93,\n", " 'is_review': False,\n", " 'journal': 'Ann. Surg. Oncol.',\n", " 'name': 'Both BRAF V600E mutation and older age (≥ 65 years) are associated with recurrent papillary thyroid cancer.',\n", " 'publication_date': {'month': 12, 'year': 2011},\n", " 'pubmed': 21594703,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21594703',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1405,\n", " 'name': 'EID1405',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Kopetz et al., 2015, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 953,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4669589',\n", " 'publication_date': {'day': 1, 'month': 12, 'year': 2015},\n", " 'pubmed': 26460303,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26460303',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Clear Cell Sarcoma',\n", " 'doid': 'DOID:4233',\n", " 'id': 966,\n", " 'name': 'Clear Cell Sarcoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4233'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3779,\n", " 'name': 'EID3779',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Protsenko et al., 2015, Invest New Drugs',\n", " 'full_journal_title': 'Investigational new drugs',\n", " 'id': 1976,\n", " 'is_review': False,\n", " 'journal': 'Invest New Drugs',\n", " 'name': 'BRAF-mutated clear cell sarcoma is sensitive to vemurafenib treatment.',\n", " 'publication_date': {'month': 10, 'year': 2015},\n", " 'pubmed': 26286452,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26286452',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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�s exact test) and had shorter 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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3738,\n", " 'name': 'EID3738',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Loupakis et al., 2009, Br. J. Cancer',\n", " 'full_journal_title': 'British journal of cancer',\n", " 'id': 1480,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Cancer',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2736831',\n", " 'publication_date': {'day': 18, 'month': 8, 'year': 2009},\n", " 'pubmed': 19603018,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19603018',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 459, 'name': 'PD 0325901'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2124,\n", " 'name': 'EID2124',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Solit et al., 2006, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 1487,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'BRAF mutation predicts sensitivity to MEK inhibition.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3306236',\n", " 'publication_date': {'day': 19, 'month': 1, 'year': 2006},\n", " 'pubmed': 16273091,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16273091',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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).',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 1552,\n", " 'name': 'EID1552',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Amaki-Takao et al., 2016, Oncology',\n", " 'full_journal_title': 'Oncology',\n", " 'id': 1027,\n", " 'is_review': False,\n", " 'journal': 'Oncology',\n", " 'name': 'Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis.',\n", " 'publication_date': {'day': 13, 'month': 7, 'year': 2016},\n", " 'pubmed': 27404270,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27404270',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Non-small Cell Lung Carcinoma',\n", " 'doid': 'DOID:3908',\n", " 'id': 8,\n", " 'name': 'Non-small Cell Lung Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3908'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'A',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3017,\n", " 'name': 'EID3017',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Planchard et al., 2016, Lancet Oncol.',\n", " 'full_journal_title': 'The Lancet. Oncology',\n", " 'id': 1296,\n", " 'is_review': False,\n", " 'journal': 'Lancet Oncol.',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4993103',\n", " 'publication_date': {'month': 7, 'year': 2016},\n", " 'pubmed': 27283860,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27283860',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Lung Adenocarcinoma',\n", " 'doid': 'DOID:3910',\n", " 'id': 26,\n", " 'name': 'Lung Adenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3910'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3782,\n", " 'name': 'EID3782',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Gautschi et al., 2015, J Thorac Oncol',\n", " 'full_journal_title': 'Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer',\n", " 'id': 1979,\n", " 'is_review': False,\n", " 'journal': 'J Thorac Oncol',\n", " 'name': 'Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort.',\n", " 'publication_date': {'month': 10, 'year': 2015},\n", " 'pubmed': 26200454,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26200454',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2504,\n", " 'name': 'EID2504',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Elisei et al., 2008, J. Clin. Endocrinol. Metab.',\n", " 'full_journal_title': 'The Journal of clinical endocrinology and metabolism',\n", " 'id': 1494,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Endocrinol. Metab.',\n", " 'name': 'BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.',\n", " 'publication_date': {'month': 10, 'year': 2008},\n", " 'pubmed': 18682506,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18682506',\n", " 'status': 'partially curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colon Cancer',\n", " 'doid': 'DOID:219',\n", " 'id': 119,\n", " 'name': 'Colon Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:219'},\n", " 'drugs': [{'id': 27, 'name': 'Regorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3776,\n", " 'name': 'EID3776',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Takigawa et al., 2016, Cancer Sci.',\n", " 'full_journal_title': 'Cancer science',\n", " 'id': 1973,\n", " 'is_review': False,\n", " 'journal': 'Cancer Sci.',\n", " 'name': 'Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5001714',\n", " 'publication_date': {'month': 5, 'year': 2016},\n", " 'pubmed': 26865419,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26865419',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2126,\n", " 'name': 'EID2126',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Long et al., 2011, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 1488,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2011},\n", " 'pubmed': 21343559,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21343559',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2122,\n", " 'name': 'EID2122',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Sharma et al., 2005, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1484,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors.',\n", " 'publication_date': {'day': 15, 'month': 3, 'year': 2005},\n", " 'pubmed': 15781657,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/15781657',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 20, 'name': 'Dasatinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3759,\n", " 'name': 'EID3759',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Woodman et al., 2009, Mol. Cancer Ther.',\n", " 'full_journal_title': 'Molecular cancer therapeutics',\n", " 'id': 74,\n", " 'is_review': False,\n", " 'journal': 'Mol. Cancer Ther.',\n", " 'name': 'Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3346953',\n", " 'publication_date': {'month': 8, 'year': 2009},\n", " 'pubmed': 19671763,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19671763',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Gastrointestinal Neuroendocrine Tumor',\n", " 'doid': 'DOID:0050626',\n", " 'id': 53,\n", " 'name': 'Gastrointestinal Neuroendocrine Tumor',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:0050626'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'},\n", " {'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1430,\n", " 'name': 'EID1430',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Klempner et al., 2016, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 969,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.',\n", " 'publication_date': {'month': 6, 'year': 2016},\n", " 'pubmed': 27048246,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27048246',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Positive',\n", " 'description': 'Thyroid nodule with BRAF V600E mutation is highly correlated with papillary thyroid cancer.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Diagnostic',\n", " 'id': 80,\n", " 'name': 'EID80',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Crescenzi et al., 2014, Horm. Metab. Res.',\n", " 'full_journal_title': 'Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme',\n", " 'id': 94,\n", " 'is_review': False,\n", " 'journal': 'Horm. Metab. Res.',\n", " 'name': 'Immunohistochemistry for BRAF(V600E) antibody VE1 performed in core needle biopsy samples identifies mutated papillary thyroid cancers.',\n", " 'publication_date': {'month': 5, 'year': 2014},\n", " 'pubmed': 24570209,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24570209',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3754,\n", " 'name': 'EID3754',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Ashworth et al., 2014, J Natl Compr Canc Netw',\n", " 'full_journal_title': 'Journal of the National Comprehensive Cancer Network : JNCCN',\n", " 'id': 1954,\n", " 'is_review': False,\n", " 'journal': 'J Natl Compr Canc Netw',\n", " 'name': 'Management of a patient with advanced BRAF-mutant melanoma.',\n", " 'publication_date': {'day': 1, 'month': 3, 'year': 2014},\n", " 'pubmed': 24616537,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24616537',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3741,\n", " 'name': 'EID3741',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Corcoran et al., 2012, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 1947,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3308191',\n", " 'publication_date': {'month': 3, 'year': 2012},\n", " 'pubmed': 22448344,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22448344',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 122, 'name': 'Selumetinib (AZD6244)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2144,\n", " 'name': 'EID2144',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Kolb et al., 2010, Pediatr Blood Cancer',\n", " 'full_journal_title': 'Pediatric blood & cancer',\n", " 'id': 1498,\n", " 'is_review': False,\n", " 'journal': 'Pediatr Blood Cancer',\n", " 'name': 'Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3004092',\n", " 'publication_date': {'month': 10, 'year': 2010},\n", " 'pubmed': 20806365,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20806365',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Non-small Cell Lung Carcinoma',\n", " 'doid': 'DOID:3908',\n", " 'id': 8,\n", " 'name': 'Non-small Cell Lung Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3908'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5958,\n", " 'name': 'EID5958',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Hainsworth et al., 2018, J. Clin. Oncol.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT02091141',\n", " '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.\",\n", " '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',\n", " 'nct_id': 'NCT02091141'}],\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2414,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.',\n", " 'publication_date': {'day': 10, 'month': 1, 'year': 2018},\n", " 'pubmed': 29320312,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29320312',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 99,\n", " 'name': 'EID99',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Yang et al., 2012, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 108,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.',\n", " 'publication_date': {'day': 1, 'month': 2, 'year': 2012},\n", " 'pubmed': 22180495,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22180495',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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 (BEZ235) and PI3K/mTOR (AZD6244 [selumetinib]) was the most effective approach to counteract resistance in comparison to inhibition with the PLX4720-BEZ235 (where response was assessed by apoptosis, viability, p-ERK, p-Akt inhibition).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 343, 'name': 'BEZ235 (NVP-BEZ235, Dactolisib)'},\n", " {'id': 122, 'name': 'Selumetinib (AZD6244)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1005,\n", " 'name': 'EID1005',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Penna et al., 2016, Oncotarget',\n", " 'full_journal_title': 'Oncotarget',\n", " 'id': 694,\n", " 'is_review': False,\n", " 'journal': 'Oncotarget',\n", " 'name': 'Primary cross-resistance to BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma cells counteracted by dual pathway blockade.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4826182',\n", " 'publication_date': {'day': 26, 'month': 1, 'year': 2016},\n", " 'pubmed': 26678033,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26678033',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3773,\n", " 'name': 'EID3773',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Dadu et al., 2015, J. Clin. Endocrinol. Metab.',\n", " 'full_journal_title': 'The Journal of clinical endocrinology and metabolism',\n", " 'id': 1970,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Endocrinol. Metab.',\n", " 'name': 'Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4283003',\n", " 'publication_date': {'month': 1, 'year': 2015},\n", " 'pubmed': 25353071,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25353071',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1591,\n", " 'name': 'EID1591',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Brose et al., 2016, Lancet Oncol.',\n", " 'full_journal_title': 'The Lancet. Oncology',\n", " 'id': 1052,\n", " 'is_review': False,\n", " 'journal': 'Lancet Oncol.',\n", " '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.',\n", " 'publication_date': {'day': 22, 'month': 7, 'year': 2016},\n", " 'pubmed': 27460442,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27460442',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3746,\n", " 'name': 'EID3746',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Nazarian et al., 2010, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 1491,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3143360',\n", " 'publication_date': {'day': 16, 'month': 12, 'year': 2010},\n", " 'pubmed': 21107323,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21107323',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Dabrafenib with trametinib provides higher response rate and lower toxicity (as compared to chemotherapy) in patients with melanoma.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 95,\n", " 'name': 'EID95',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Menzies et al., 2014, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 105,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma.',\n", " 'publication_date': {'day': 15, 'month': 4, 'year': 2014},\n", " 'pubmed': 24583796,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24583796',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3742,\n", " 'name': 'EID3742',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hyman et al., 2015, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1040,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4971773',\n", " 'publication_date': {'day': 20, 'month': 8, 'year': 2015},\n", " 'pubmed': 26287849,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26287849',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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�s exact test).',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3763,\n", " 'name': 'EID3763',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Schiffman et al., 2010, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1961,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2851233',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2010},\n", " 'pubmed': 20068183,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20068183',\n", " 'status': 'fully curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Skin Melanoma',\n", " 'doid': 'DOID:8923',\n", " 'id': 206,\n", " 'name': 'Skin Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:8923'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2146,\n", " 'name': 'EID2146',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hauschild et al., 2012, Lancet',\n", " 'full_journal_title': 'Lancet (London, England)',\n", " 'id': 1500,\n", " 'is_review': False,\n", " 'journal': 'Lancet',\n", " 'name': 'Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.',\n", " 'publication_date': {'day': 28, 'month': 7, 'year': 2012},\n", " 'pubmed': 22735384,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22735384',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3745,\n", " 'name': 'EID3745',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Johannessen et al., 2010, Nature',\n", " 'full_journal_title': 'Nature',\n", " 'id': 1492,\n", " 'is_review': False,\n", " 'journal': 'Nature',\n", " 'name': 'COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3058384',\n", " 'publication_date': {'day': 16, 'month': 12, 'year': 2010},\n", " 'pubmed': 21107320,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21107320',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6938,\n", " 'name': 'EID6938',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Long et al., 2014, N. Engl. J. Med.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT01584648',\n", " '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.',\n", " 'name': 'A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma',\n", " 'nct_id': 'NCT01584648'}],\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 2671,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.',\n", " 'publication_date': {'day': 13, 'month': 11, 'year': 2014},\n", " 'pubmed': 25265492,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25265492',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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�M). Sensitivity was determined by assessing growth inhibition.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3756,\n", " 'name': 'EID3756',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Vergani et al., 2011, Neoplasia',\n", " 'full_journal_title': 'Neoplasia (New York, N.Y.)',\n", " 'id': 1956,\n", " 'is_review': False,\n", " 'journal': 'Neoplasia',\n", " 'name': 'Identification of MET and SRC activation in melanoma cell lines showing primary resistance to PLX4032.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3257188',\n", " 'publication_date': {'month': 12, 'year': 2011},\n", " 'pubmed': 22241959,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22241959',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 31, 'name': 'Nutlin-3'}, {'id': 30, 'name': 'PLX4720'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 97,\n", " 'name': 'EID97',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Ji et al., 2013, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 107,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3777641',\n", " 'publication_date': {'day': 15, 'month': 8, 'year': 2013},\n", " 'pubmed': 23812671,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23812671',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'Acquired resistance to vemurafenib in BRAF-V600E positive melanomas frequently confound vemurafenib therapy.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2127,\n", " 'name': 'EID2127',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Flaherty et al., 2010, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 352,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Inhibition of mutated, activated BRAF in metastatic melanoma.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3724529',\n", " 'publication_date': {'day': 26, 'month': 8, 'year': 2010},\n", " 'pubmed': 20818844,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20818844',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " 'description': 'Chemotherapy-refractory patients with colorectal cancer harboring BRAF mutations had lower response and disease control rates as well as shorter progression free and overall survival following cetuximab plus chemotherapy than those with wildtype BRAF.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 126,\n", " 'name': 'EID126',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'De Roock et al., 2010, Lancet Oncol.',\n", " 'full_journal_title': 'The Lancet. Oncology',\n", " 'id': 76,\n", " 'is_review': False,\n", " 'journal': 'Lancet Oncol.',\n", " '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.',\n", " 'publication_date': {'month': 8, 'year': 2010},\n", " 'pubmed': 20619739,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20619739',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Malignant Peripheral Nerve Sheath Tumor',\n", " 'doid': 'DOID:5940',\n", " 'id': 326,\n", " 'name': 'Malignant Peripheral Nerve Sheath Tumor',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:5940'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3788,\n", " 'name': 'EID3788',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Kaplan, 2013, J Natl Compr Canc Netw',\n", " 'full_journal_title': 'Journal of the National Comprehensive Cancer Network : JNCCN',\n", " 'id': 1958,\n", " 'is_review': False,\n", " 'journal': 'J Natl Compr Canc Netw',\n", " 'name': 'Vemurafenib treatment of BRAF V600E-mutated malignant peripheral nerve sheath tumor.',\n", " 'publication_date': {'day': 1, 'month': 12, 'year': 2013},\n", " 'pubmed': 24335681,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24335681',\n", " 'status': 'submitted'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Adenocarcinoma',\n", " 'doid': 'DOID:0050861',\n", " 'id': 57,\n", " 'name': 'Colorectal Adenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:0050861'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 28, 'name': 'Panitumumab'},\n", " {'id': 19, 'name': 'Trametinib'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6124,\n", " 'name': 'EID6124',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Corcoran et al., 2018, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 2468,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " 'name': 'Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5882509',\n", " 'publication_date': {'month': 4, 'year': 2018},\n", " 'pubmed': 29431699,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29431699',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'In a clinical study of Polish, stage IIIC/IV, melanoma patients with metastases (n=75) harboring BRAF V600 mutation (as detected by cobas 4800 BRAF V600 Mutation Test), patients were associated with a 61.9% (95% CI: 50.1-73.6) median overall survival, a 7.4 months (95% CI: 5.5-9.2) median progression free survival; a median duration response of 7.4 months was reported, with 3% (2/75) and 43% (29/75) of patients achieving a complete and partial response, respectively.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3755,\n", " 'name': 'EID3755',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Rutkowski et al., 2015, Contemp Oncol (Pozn)',\n", " 'full_journal_title': 'Contemporary oncology (Poznan, Poland)',\n", " 'id': 1955,\n", " 'is_review': False,\n", " 'journal': 'Contemp Oncol (Pozn)',\n", " 'name': 'The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4631301',\n", " 'publication_date': {'year': 2015},\n", " 'pubmed': 26557775,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26557775',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 28, 'name': 'Panitumumab'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1413,\n", " 'name': 'EID1413',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Yaeger et al., 2015, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 957,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.',\n", " 'publication_date': {'day': 15, 'month': 3, 'year': 2015},\n", " 'pubmed': 25589621,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25589621',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1406,\n", " 'name': 'EID1406',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Falchook et al., 2012, Lancet',\n", " 'full_journal_title': 'Lancet (London, England)',\n", " 'id': 345,\n", " 'is_review': False,\n", " 'journal': 'Lancet',\n", " 'name': 'Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4109288',\n", " 'publication_date': {'day': 19, 'month': 5, 'year': 2012},\n", " 'pubmed': 22608338,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22608338',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Malignant Conjunctival Melanoma',\n", " 'doid': 'DOID:1751',\n", " 'id': 2605,\n", " 'name': 'Malignant Conjunctival Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1751'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3790,\n", " 'name': 'EID3790',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Maleka et al., 2016, BMC Cancer',\n", " 'full_journal_title': 'BMC cancer',\n", " 'id': 1986,\n", " 'is_review': False,\n", " 'journal': 'BMC Cancer',\n", " 'name': 'A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4983009',\n", " 'publication_date': {'day': 12, 'month': 8, 'year': 2016},\n", " 'pubmed': 27520988,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27520988',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3753,\n", " 'name': 'EID3753',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Yang et al., 2010, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 351,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models.',\n", " 'publication_date': {'day': 1, 'month': 7, 'year': 2010},\n", " 'pubmed': 20551065,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20551065',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3767,\n", " 'name': 'EID3767',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Peyrade et al., 2013, Haematologica',\n", " 'full_journal_title': 'Haematologica',\n", " 'id': 1964,\n", " 'is_review': False,\n", " 'journal': 'Haematologica',\n", " 'name': 'Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3561446',\n", " 'publication_date': {'month': 2, 'year': 2013},\n", " 'pubmed': 23300174,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23300174',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Thyroid Carcinoma',\n", " 'doid': 'DOID:3963',\n", " 'id': 155,\n", " 'name': 'Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3963'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3785,\n", " 'name': 'EID3785',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Byeon et al., 2016, Mol. Carcinog.',\n", " 'full_journal_title': 'Molecular carcinogenesis',\n", " 'id': 1982,\n", " 'is_review': False,\n", " 'journal': 'Mol. Carcinog.',\n", " 'name': 'c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.',\n", " 'publication_date': {'month': 11, 'year': 2016},\n", " 'pubmed': 26456083,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26456083',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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).',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 237, 'name': 'Oxaliplatin'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2117,\n", " 'name': 'EID2117',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Souglakos et al., 2009, Br. J. Cancer',\n", " 'full_journal_title': 'British journal of cancer',\n", " 'id': 1479,\n", " 'is_review': False,\n", " 'journal': 'Br. J. Cancer',\n", " 'name': 'Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2720232',\n", " 'publication_date': {'day': 4, 'month': 8, 'year': 2009},\n", " 'pubmed': 19603024,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19603024',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Positive',\n", " 'description': 'BRAF V600E is shown to be associated with the tall-cell variant of papillary thyroid cancer.',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Diagnostic',\n", " 'id': 79,\n", " 'name': 'EID79',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Howell et al., 2011, Ann. Surg. Oncol.',\n", " 'full_journal_title': 'Annals of surgical oncology',\n", " 'id': 93,\n", " 'is_review': False,\n", " 'journal': 'Ann. Surg. Oncol.',\n", " 'name': 'Both BRAF V600E mutation and older age (≥ 65 years) are associated with recurrent papillary thyroid cancer.',\n", " 'publication_date': {'month': 12, 'year': 2011},\n", " 'pubmed': 21594703,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21594703',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " 'description': 'In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP and resistance to RAF inhibitors.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 90,\n", " 'name': 'EID90',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Nissan et al., 2014, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 98,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4005042',\n", " 'publication_date': {'day': 15, 'month': 4, 'year': 2014},\n", " 'pubmed': 24576830,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24576830',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6178,\n", " 'name': 'EID6178',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Long et al., 2017, N. Engl. J. Med.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT01682083',\n", " '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.',\n", " '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.',\n", " 'nct_id': 'NCT01682083'}],\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 2475,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.',\n", " 'publication_date': {'day': 9, 'year': 2017},\n", " 'pubmed': 28891408,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/28891408',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Histiocytoma',\n", " 'doid': 'DOID:4231',\n", " 'id': 964,\n", " 'name': 'Histiocytoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4231'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3789,\n", " 'name': 'EID3789',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Idbaih et al., 2014, Neurology',\n", " 'full_journal_title': 'Neurology',\n", " 'id': 1985,\n", " 'is_review': False,\n", " 'journal': 'Neurology',\n", " 'name': 'Dramatic response of a BRAF V600E-mutated primary CNS histiocytic sarcoma to vemurafenib.',\n", " 'publication_date': {'day': 14, 'month': 10, 'year': 2014},\n", " 'pubmed': 25209580,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25209580',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 463, 'name': 'RDEA 119'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2139,\n", " 'name': 'EID2139',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Liu et al., 2010, Int. J. Cancer',\n", " 'full_journal_title': 'International journal of cancer',\n", " 'id': 1496,\n", " 'is_review': False,\n", " 'journal': 'Int. J. Cancer',\n", " 'name': 'BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2916062',\n", " 'publication_date': {'day': 15, 'month': 12, 'year': 2010},\n", " 'pubmed': 21351275,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21351275',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'In a phase 2 “basket” 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%.',\n", " 'disease': {'display_name': 'Anaplastic Thyroid Carcinoma',\n", " 'id': 2952,\n", " 'name': 'Anaplastic Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6045,\n", " 'name': 'EID6045',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Hyman et al., 2015, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1040,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4971773',\n", " 'publication_date': {'day': 20, 'month': 8, 'year': 2015},\n", " 'pubmed': 26287849,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26287849',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2128,\n", " 'name': 'EID2128',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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%.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1579,\n", " 'name': 'EID1579',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Tiacci et al., 2015, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1043,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4811324',\n", " 'publication_date': {'day': 29, 'month': 10, 'year': 2015},\n", " 'pubmed': 26352686,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26352686',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 122, 'name': 'Selumetinib (AZD6244)'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2129,\n", " 'name': 'EID2129',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Haass et al., 2008, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 1489,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " '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.',\n", " 'publication_date': {'day': 1, 'month': 1, 'year': 2008},\n", " 'pubmed': 18172275,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18172275',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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�s metastases demonstrated significant response and pleural right effusion improvement was observed; however, at 4 months the patient�s disease progressed resulting in death.',\n", " 'disease': {'display_name': 'Lung Adenocarcinoma',\n", " 'doid': 'DOID:3910',\n", " 'id': 26,\n", " 'name': 'Lung Adenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3910'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3780,\n", " 'name': 'EID3780',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Robinson et al., 2014, Lung Cancer',\n", " 'full_journal_title': 'Lung cancer (Amsterdam, Netherlands)',\n", " 'id': 1977,\n", " 'is_review': False,\n", " 'journal': 'Lung Cancer',\n", " 'name': 'BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib.',\n", " 'publication_date': {'month': 8, 'year': 2014},\n", " 'pubmed': 24888229,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24888229',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 103,\n", " 'name': 'EID103',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Chen et al., 2014, PLoS ONE',\n", " 'full_journal_title': 'PloS one',\n", " 'id': 110,\n", " 'is_review': False,\n", " 'journal': 'PLoS ONE',\n", " 'name': 'BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3940924',\n", " 'publication_date': {'year': 2014},\n", " 'pubmed': 24594804,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24594804',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3736,\n", " 'name': 'EID3736',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Laurent-Puig et al., 2009, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 1945,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.',\n", " 'publication_date': {'day': 10, 'month': 12, 'year': 2009},\n", " 'pubmed': 19884556,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19884556',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3769,\n", " 'name': 'EID3769',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Bailleux et al., 2015, Oncoscience',\n", " 'full_journal_title': 'Oncoscience',\n", " 'id': 1966,\n", " 'is_review': False,\n", " 'journal': 'Oncoscience',\n", " 'name': 'Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4341463',\n", " 'publication_date': {'year': 2015},\n", " 'pubmed': 25815361,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25815361',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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)',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1398,\n", " 'name': 'EID1398',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'McArthur et al., 2014, Lancet Oncol.',\n", " 'full_journal_title': 'The Lancet. Oncology',\n", " 'id': 947,\n", " 'is_review': False,\n", " 'journal': 'Lancet Oncol.',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4382632',\n", " 'publication_date': {'month': 3, 'year': 2014},\n", " 'pubmed': 24508103,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24508103',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3752,\n", " 'name': 'EID3752',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Porcelli et al., 2015, Cancer Chemother. Pharmacol.',\n", " 'full_journal_title': 'Cancer chemotherapy and pharmacology',\n", " 'id': 1953,\n", " 'is_review': False,\n", " 'journal': 'Cancer Chemother. Pharmacol.',\n", " 'name': 'Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel better than vemurafenib?',\n", " 'publication_date': {'month': 8, 'year': 2015},\n", " 'pubmed': 26070258,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26070258',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3770,\n", " 'name': 'EID3770',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'McDowell et al., 2016, Leuk. Lymphoma',\n", " 'full_journal_title': 'Leukemia & lymphoma',\n", " 'id': 1967,\n", " 'is_review': False,\n", " 'journal': 'Leuk. Lymphoma',\n", " 'name': 'Response of relapsed central nervous system hairy cell leukemia to vemurafenib.',\n", " 'publication_date': {'month': 12, 'year': 2016},\n", " 'pubmed': 27116997,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27116997',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Ovarian Cancer',\n", " 'doid': 'DOID:2394',\n", " 'id': 20,\n", " 'name': 'Ovarian Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:2394'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5959,\n", " 'name': 'EID5959',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Hainsworth et al., 2018, J. Clin. Oncol.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT02091141',\n", " '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.\",\n", " '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',\n", " 'nct_id': 'NCT02091141'}],\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2414,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.',\n", " 'publication_date': {'day': 10, 'month': 1, 'year': 2018},\n", " 'pubmed': 29320312,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29320312',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Skin Melanoma',\n", " 'doid': 'DOID:8923',\n", " 'id': 206,\n", " 'name': 'Skin Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:8923'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'A',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1409,\n", " 'name': 'EID1409',\n", " 'open_change_count': 0,\n", " 'rating': 5,\n", " 'source': {'citation': 'Chapman et al., 2011, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 954,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Improved survival with vemurafenib in melanoma with BRAF V600E mutation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3549296',\n", " 'publication_date': {'day': 30, 'month': 6, 'year': 2011},\n", " 'pubmed': 21639808,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21639808',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'},\n", " {'id': 22, 'name': 'Dabrafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 6940,\n", " 'name': 'EID6940',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Flaherty et al., 2012, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 103,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3549295',\n", " 'publication_date': {'month': 11, 'year': 2012},\n", " 'pubmed': 23020132,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23020132',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3774,\n", " 'name': 'EID3774',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Kim et al., 2013, Thyroid',\n", " 'full_journal_title': 'Thyroid : official journal of the American Thyroid Association',\n", " 'id': 1971,\n", " 'is_review': False,\n", " 'journal': 'Thyroid',\n", " 'name': 'Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3967415',\n", " 'publication_date': {'month': 10, 'year': 2013},\n", " 'pubmed': 23489023,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23489023',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Non-small Cell Lung Carcinoma',\n", " 'doid': 'DOID:3908',\n", " 'id': 8,\n", " 'name': 'Non-small Cell Lung Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3908'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3761,\n", " 'name': 'EID3761',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Joshi et al., 2015, PLoS ONE',\n", " 'full_journal_title': 'PloS one',\n", " 'id': 1960,\n", " 'is_review': False,\n", " 'journal': 'PLoS ONE',\n", " 'name': 'Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4338247',\n", " 'publication_date': {'year': 2015},\n", " 'pubmed': 25706985,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25706985',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 463, 'name': 'RDEA 119'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2141,\n", " 'name': 'EID2141',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Elisei et al., 2008, J. Clin. Endocrinol. Metab.',\n", " 'full_journal_title': 'The Journal of clinical endocrinology and metabolism',\n", " 'id': 1494,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Endocrinol. Metab.',\n", " 'name': 'BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.',\n", " 'publication_date': {'month': 10, 'year': 2008},\n", " 'pubmed': 18682506,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18682506',\n", " 'status': 'partially curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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�s exact test).',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3764,\n", " 'name': 'EID3764',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Schindler et al., 2011, Acta Neuropathol.',\n", " 'full_journal_title': 'Acta neuropathologica',\n", " 'id': 1962,\n", " 'is_review': False,\n", " 'journal': 'Acta Neuropathol.',\n", " '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.',\n", " 'publication_date': {'month': 3, 'year': 2011},\n", " 'pubmed': 21274720,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21274720',\n", " 'status': 'fully curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " 'description': 'In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP but does not show resistance to MEK inhibitors.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Substitutes',\n", " 'drugs': [{'id': 29, 'name': 'PD0325901'},\n", " {'id': 19, 'name': 'Trametinib'}],\n", " 'evidence_direction': 'Does Not Support',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 86,\n", " 'name': 'EID86',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Nissan et al., 2014, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 98,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4005042',\n", " 'publication_date': {'day': 15, 'month': 4, 'year': 2014},\n", " 'pubmed': 24576830,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24576830',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 461, 'name': 'GSK 1120212'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2131,\n", " 'name': 'EID2131',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Skin Melanoma',\n", " 'doid': 'DOID:8923',\n", " 'id': 206,\n", " 'name': 'Skin Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:8923'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1410,\n", " 'name': 'EID1410',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Sosman et al., 2012, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 354,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3724515',\n", " 'publication_date': {'day': 23, 'month': 2, 'year': 2012},\n", " 'pubmed': 22356324,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22356324',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Non-small Cell Lung Carcinoma',\n", " 'doid': 'DOID:3908',\n", " 'id': 8,\n", " 'name': 'Non-small Cell Lung Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3908'},\n", " 'drugs': [{'id': 459, 'name': 'PD 0325901'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2143,\n", " 'name': 'EID2143',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Pratilas et al., 2008, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 341,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Genetic predictors of MEK dependence in non-small cell lung cancer.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2649746',\n", " 'publication_date': {'day': 15, 'month': 11, 'year': 2008},\n", " 'pubmed': 19010912,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/19010912',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " 'description': 'BRAF mutation correlated with poor prognosis in papillary thyroid cancer in both older (>65 yo) and younger (<65 yo) cohorts.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 105,\n", " 'name': 'EID105',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Howell et al., 2011, Ann. Surg. Oncol.',\n", " 'full_journal_title': 'Annals of surgical oncology',\n", " 'id': 93,\n", " 'is_review': False,\n", " 'journal': 'Ann. Surg. Oncol.',\n", " 'name': 'Both BRAF V600E mutation and older age (≥ 65 years) are associated with recurrent papillary thyroid cancer.',\n", " 'publication_date': {'month': 12, 'year': 2011},\n", " 'pubmed': 21594703,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21594703',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Resistance',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drugs': [{'id': 16, 'name': 'Cetuximab'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3740,\n", " 'name': 'EID3740',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hsu et al., 2016, Oncotarget',\n", " 'full_journal_title': 'Oncotarget',\n", " 'id': 1946,\n", " 'is_review': False,\n", " 'journal': 'Oncotarget',\n", " 'name': 'Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC5008360',\n", " 'publication_date': {'day': 19, 'month': 4, 'year': 2016},\n", " 'pubmed': 26989027,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26989027',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Ganglioglioma',\n", " 'doid': 'DOID:5078',\n", " 'id': 2604,\n", " 'name': 'Ganglioglioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:5078'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3778,\n", " 'name': 'EID3778',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Aguilera et al., 2016, Pediatr Blood Cancer',\n", " 'full_journal_title': 'Pediatric blood & cancer',\n", " 'id': 1975,\n", " 'is_review': False,\n", " 'journal': 'Pediatr Blood Cancer',\n", " 'name': 'Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.',\n", " 'publication_date': {'month': 3, 'year': 2016},\n", " 'pubmed': 26579623,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26579623',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Pilocytic Astrocytoma',\n", " 'doid': 'DOID:4851',\n", " 'id': 166,\n", " 'name': 'Pilocytic Astrocytoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4851'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3772,\n", " 'name': 'EID3772',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Skrypek et al., 2014, Pediatr Blood Cancer',\n", " 'full_journal_title': 'Pediatric blood & cancer',\n", " 'id': 1969,\n", " 'is_review': False,\n", " 'journal': 'Pediatr Blood Cancer',\n", " 'name': 'Pilomyxoid astrocytoma treated successfully with vemurafenib.',\n", " 'publication_date': {'month': 11, 'year': 2014},\n", " 'pubmed': 24821190,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/24821190',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3748,\n", " 'name': 'EID3748',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3766,\n", " 'name': 'EID3766',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Dietrich et al., 2012, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1963,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'BRAF inhibition in refractory hairy-cell leukemia.',\n", " 'publication_date': {'day': 24, 'month': 5, 'year': 2012},\n", " 'pubmed': 22621641,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22621641',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'A stage IV lung adenocarcinoma patient harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient�s 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.',\n", " 'disease': {'display_name': 'Lung Adenocarcinoma',\n", " 'doid': 'DOID:3910',\n", " 'id': 26,\n", " 'name': 'Lung Adenocarcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3910'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3783,\n", " 'name': 'EID3783',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Myall et al., 2016, Clin Lung Cancer',\n", " 'full_journal_title': 'Clinical lung cancer',\n", " 'id': 1980,\n", " 'is_review': False,\n", " 'journal': 'Clin Lung Cancer',\n", " 'name': 'Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene.',\n", " 'publication_date': {'month': 3, 'year': 2016},\n", " 'pubmed': 26776917,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/26776917',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3765,\n", " 'name': 'EID3765',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Horbinski et al., 2012, Neuro-oncology',\n", " 'full_journal_title': 'Neuro-oncology',\n", " 'id': 1499,\n", " 'is_review': False,\n", " 'journal': 'Neuro-oncology',\n", " 'name': 'Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3367847',\n", " 'publication_date': {'month': 6, 'year': 2012},\n", " 'pubmed': 22492957,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22492957',\n", " 'status': 'fully curated'},\n", " 'status': 'rejected',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Laryngeal Squamous Cell Carcinoma',\n", " 'doid': 'DOID:2876',\n", " 'id': 124,\n", " 'name': 'Laryngeal Squamous Cell Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:2876'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 5962,\n", " 'name': 'EID5962',\n", " 'open_change_count': 0,\n", " 'rating': 3,\n", " 'source': {'citation': 'Hainsworth et al., 2018, J. Clin. Oncol.',\n", " 'clinical_trials': [{'clinical_trial_url': 'https://clinicaltrials.gov/show/NCT02091141',\n", " '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.\",\n", " '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',\n", " 'nct_id': 'NCT02091141'}],\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 2414,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.',\n", " 'publication_date': {'day': 10, 'month': 1, 'year': 2018},\n", " 'pubmed': 29320312,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/29320312',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Positive',\n", " 'description': 'In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E mutation in all 47 of the sequenced patients.',\n", " 'disease': {'display_name': 'Hairy Cell Leukemia',\n", " 'doid': 'DOID:285',\n", " 'id': 665,\n", " 'name': 'Hairy Cell Leukemia',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:285'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Diagnostic',\n", " 'id': 1127,\n", " 'name': 'EID1127',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Tiacci et al., 2011, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 780,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'BRAF mutations in hairy-cell leukemia.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3689585',\n", " 'publication_date': {'day': 16, 'month': 6, 'year': 2011},\n", " 'pubmed': 21663470,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/21663470',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Pleomorphic Xanthoastrocytoma',\n", " 'doid': 'DOID:4852',\n", " 'id': 1124,\n", " 'name': 'Pleomorphic Xanthoastrocytoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:4852'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3786,\n", " 'name': 'EID3786',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Lee et al., 2016, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 1983,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Successful Treatment of a Progressive BRAF V600E-Mutated Anaplastic Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy.',\n", " 'publication_date': {'day': 1, 'month': 4, 'year': 2016},\n", " 'pubmed': 25092772,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25092772',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model shows a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 19, 'name': 'Trametinib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2134,\n", " 'name': 'EID2134',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3750,\n", " 'name': 'EID3750',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Trunzer et al., 2013, J. Clin. Oncol.',\n", " 'full_journal_title': 'Journal of clinical oncology : official journal of the American Society of Clinical Oncology',\n", " 'id': 60,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Oncol.',\n", " 'name': 'Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.',\n", " 'publication_date': {'day': 10, 'month': 5, 'year': 2013},\n", " 'pubmed': 23569304,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23569304',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3747,\n", " 'name': 'EID3747',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Halaban et al., 2010, Pigment Cell Melanoma Res',\n", " 'full_journal_title': 'Pigment cell & melanoma research',\n", " 'id': 1482,\n", " 'is_review': False,\n", " 'journal': 'Pigment Cell Melanoma Res',\n", " 'name': 'PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2848976',\n", " 'publication_date': {'month': 4, 'year': 2010},\n", " 'pubmed': 20149136,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/20149136',\n", " 'status': 'submitted'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " 'description': 'An inducible BRAF-V600E mouse melanoma model has shown a tight correlation between activated BRAF and disease progression.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2123,\n", " 'name': 'EID2123',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Hoeflich et al., 2006, Cancer Res.',\n", " 'full_journal_title': 'Cancer research',\n", " 'id': 1485,\n", " 'is_review': False,\n", " 'journal': 'Cancer Res.',\n", " 'name': 'Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.',\n", " 'publication_date': {'day': 15, 'month': 1, 'year': 2006},\n", " 'pubmed': 16424035,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16424035',\n", " 'status': 'partially curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 141, 'name': 'Pictilisib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 757,\n", " 'name': 'EID757',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Sarker et al., 2015, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 500,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " '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.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC4287394',\n", " 'publication_date': {'day': 1, 'month': 1, 'year': 2015},\n", " 'pubmed': 25370471,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25370471',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Thyroid Cancer',\n", " 'doid': 'DOID:1781',\n", " 'id': 16,\n", " 'name': 'Thyroid Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1781'},\n", " 'drugs': [{'id': 6, 'name': 'Sorafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 2142,\n", " 'name': 'EID2142',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Salvatore et al., 2006, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 1497,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'BRAF is a therapeutic target in aggressive thyroid carcinoma.',\n", " 'publication_date': {'day': 1, 'month': 3, 'year': 2006},\n", " 'pubmed': 16533790,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/16533790',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 342, 'name': 'Cobimetinib'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1421,\n", " 'name': 'EID1421',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Larkin et al., 2014, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 963,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.',\n", " 'publication_date': {'day': 13, 'month': 11, 'year': 2014},\n", " 'pubmed': 25265494,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/25265494',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Colorectal Cancer',\n", " 'doid': 'DOID:9256',\n", " 'id': 11,\n", " 'name': 'Colorectal Cancer',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:9256'},\n", " 'drug_interaction_type': 'Combination',\n", " 'drugs': [{'id': 28, 'name': 'Panitumumab'},\n", " {'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 1589,\n", " 'name': 'EID1589',\n", " 'open_change_count': 0,\n", " 'rating': 2,\n", " 'source': {'citation': 'Pietrantonio et al., 2016, Cancer Discov',\n", " 'full_journal_title': 'Cancer discovery',\n", " 'id': 1050,\n", " 'is_review': False,\n", " 'journal': 'Cancer Discov',\n", " '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.',\n", " 'publication_date': {'day': 20, 'month': 6, 'year': 2016},\n", " 'pubmed': 27325282,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/27325282',\n", " 'status': 'fully curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'description': 'An anaplastic thyroid cancer patient harboring BRAF V600E mutation was associated with response to vemurafenib treatment. The patient was initially treated with paclitaxel, but experienced disease progression; subsequently, the patient was treated concurrently with vemurafenib and radiation therapy and achieved regression of metastatic disease.',\n", " 'disease': {'display_name': 'Thyroid Carcinoma',\n", " 'doid': 'DOID:3963',\n", " 'id': 155,\n", " 'name': 'Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3963'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_level': 'C',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3743,\n", " 'name': 'EID3743',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Rosove et al., 2013, N. Engl. J. Med.',\n", " 'full_journal_title': 'The New England journal of medicine',\n", " 'id': 1948,\n", " 'is_review': False,\n", " 'journal': 'N. Engl. J. Med.',\n", " 'name': 'BRAF V600E inhibition in anaplastic thyroid cancer.',\n", " 'publication_date': {'day': 14, 'month': 2, 'year': 2013},\n", " 'pubmed': 23406047,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/23406047',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Poor Outcome',\n", " '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.',\n", " 'disease': {'display_name': 'Papillary Thyroid Carcinoma',\n", " 'doid': 'DOID:3969',\n", " 'id': 156,\n", " 'name': 'Papillary Thyroid Carcinoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3969'},\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'B',\n", " 'evidence_type': 'Prognostic',\n", " 'id': 2137,\n", " 'name': 'EID2137',\n", " 'open_change_count': 0,\n", " 'rating': 4,\n", " 'source': {'citation': 'Elisei et al., 2008, J. Clin. Endocrinol. Metab.',\n", " 'full_journal_title': 'The Journal of clinical endocrinology and metabolism',\n", " 'id': 1494,\n", " 'is_review': False,\n", " 'journal': 'J. Clin. Endocrinol. Metab.',\n", " 'name': 'BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.',\n", " 'publication_date': {'month': 10, 'year': 2008},\n", " 'pubmed': 18682506,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18682506',\n", " 'status': 'partially curated'},\n", " 'status': 'accepted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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).',\n", " 'disease': {'display_name': 'Malignant Glioma',\n", " 'doid': 'DOID:3070',\n", " 'id': 695,\n", " 'name': 'Malignant Glioma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:3070'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3762,\n", " 'name': 'EID3762',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Nicolaides et al., 2011, Clin. Cancer Res.',\n", " 'full_journal_title': 'Clinical cancer research : an official journal of the American Association for Cancer Research',\n", " 'id': 348,\n", " 'is_review': False,\n", " 'journal': 'Clin. Cancer Res.',\n", " 'name': 'Targeted therapy for BRAFV600E malignant astrocytoma.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC3638050',\n", " 'publication_date': {'day': 15, 'month': 12, 'year': 2011},\n", " 'pubmed': 22038996,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/22038996',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'},\n", " {'clinical_significance': 'Sensitivity/Response',\n", " '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.',\n", " 'disease': {'display_name': 'Melanoma',\n", " 'doid': 'DOID:1909',\n", " 'id': 7,\n", " 'name': 'Melanoma',\n", " 'url': 'http://www.disease-ontology.org/?id=DOID:1909'},\n", " 'drugs': [{'id': 4, 'name': 'Vemurafenib'}],\n", " 'evidence_direction': 'Supports',\n", " 'evidence_level': 'D',\n", " 'evidence_type': 'Predictive',\n", " 'id': 3751,\n", " 'name': 'EID3751',\n", " 'open_change_count': 0,\n", " 'source': {'citation': 'Tsai et al., 2008, Proc. Natl. Acad. Sci. U.S.A.',\n", " 'full_journal_title': 'Proceedings of the National Academy of Sciences of the United States of America',\n", " 'id': 1952,\n", " 'is_review': False,\n", " 'journal': 'Proc. Natl. Acad. Sci. U.S.A.',\n", " 'name': 'Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.',\n", " 'open_access': True,\n", " 'pmc_id': 'PMC2268581',\n", " 'publication_date': {'day': 26, 'month': 2, 'year': 2008},\n", " 'pubmed': 18287029,\n", " 'source_url': 'http://www.ncbi.nlm.nih.gov/pubmed/18287029',\n", " 'status': 'fully curated'},\n", " 'status': 'submitted',\n", " 'type': 'evidence',\n", " 'variant_id': 12,\n", " 'variant_origin': 'Somatic Mutation'}],\n", " 'gene_id': 5,\n", " 'hgvs_expressions': ['NM_004333.4:c.1799T>A',\n", " 'NP_004324.2:p.Val600Glu',\n", " 'NC_000007.13:g.140453136A>T',\n", " 'ENST00000288602.6:c.1799T>A'],\n", " 'lifecycle_actions': {'last_commented_on': {'timestamp': '2017-05-14T03:50:30.104Z',\n", " 'user': {'area_of_expertise': 'Research Scientist',\n", " 'avatar_url': 'https://secure.gravatar.com/avatar/4c468e9a95d6135e02eb66ee5f2fb574.png?d=identicon&r=pg&s=32',\n", " 'avatars': {'x128': 'https://secure.gravatar.com/avatar/4c468e9a95d6135e02eb66ee5f2fb574.png?d=identicon&r=pg&s=128',\n", " 'x14': 'https://secure.gravatar.com/avatar/4c468e9a95d6135e02eb66ee5f2fb574.png?d=identicon&r=pg&s=14',\n", " 'x32': 'https://secure.gravatar.com/avatar/4c468e9a95d6135e02eb66ee5f2fb574.png?d=identicon&r=pg&s=32',\n", " 'x64': 'https://secure.gravatar.com/avatar/4c468e9a95d6135e02eb66ee5f2fb574.png?d=identicon&r=pg&s=64'},\n", " 'bio': 'Dr. Griffith is Assistant Professor of Medicine and Assistant Director of the McDonnell Genome Institute at Washington University School of Medicine. He has worked in genomics and bioinformatics since the earliest phase of reference genome sequencing. He contributed to the Mammalian Gene Collection, producing some of the first full-length sequences for many human genes. He also was part of a small team of bioinformaticians that helped sequence and release the first whole genome reference sequence for the severe acute respiratory syndrome (SARS) virus at the height of the 2003 epidemic. He has contributed to the identification of molecular markers at the DNA, RNA and protein level that are useful for diagnosis and prognosis of thyroid, breast, lymphoma and other cancers. His lab’s research is focused on the development of informatics resources and personalized medicine strategies for cancer using genomic technologies. He is a co-creator of the CIViC resource.',\n", " 'created_at': '2015-02-26T02:53:49.147Z',\n", " 'display_name': 'obigriffith',\n", " 'featured_expert': True,\n", " 'id': 3,\n", " 'last_seen_at': '2019-02-28T20:39:46.357Z',\n", " 'linkedin_profile': 'obigriffith',\n", " 'name': 'Obi Griffith',\n", " 'orcid': '0000-0002-0843-4271',\n", " 'organization': {'description': 'The McDonnell Genome Institute (MGI) is a world leader in the fast-paced, constantly changing field of genomics. A truly unique institution, we are pushing the limits of academic research by creating, testing, and implementing new approaches to the study of biology with the goal of understanding human health and disease, as well as evolution and the biology of other organisms.',\n", " 'id': 1,\n", " 'name': 'The McDonnell Genome Institute',\n", " 'profile_image': {'x128': '/system/organizations/profile_images/000/000/001/x128/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x14': '/system/organizations/profile_images/000/000/001/x14/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x256': '/system/organizations/profile_images/000/000/001/x256/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x32': '/system/organizations/profile_images/000/000/001/x32/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x64': '/system/organizations/profile_images/000/000/001/x64/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976'},\n", " 'url': 'http://genome.wustl.edu/'},\n", " 'role': 'admin',\n", " 'twitter_handle': 'obigriffith',\n", " 'url': 'http://genome.wustl.edu/people/individual/obi-griffith/',\n", " 'username': 'obigriffith'}},\n", " 'last_modified': {'timestamp': '2017-04-02T14:56:18.921Z',\n", " 'user': {'area_of_expertise': 'Research Scientist',\n", " 'avatar_url': 'https://secure.gravatar.com/avatar/17180f9afc9f7f04fff97197c1ee5cb6.png?d=identicon&r=pg&s=32',\n", " 'avatars': {'x128': 'https://secure.gravatar.com/avatar/17180f9afc9f7f04fff97197c1ee5cb6.png?d=identicon&r=pg&s=128',\n", " 'x14': 'https://secure.gravatar.com/avatar/17180f9afc9f7f04fff97197c1ee5cb6.png?d=identicon&r=pg&s=14',\n", " 'x32': 'https://secure.gravatar.com/avatar/17180f9afc9f7f04fff97197c1ee5cb6.png?d=identicon&r=pg&s=32',\n", " 'x64': 'https://secure.gravatar.com/avatar/17180f9afc9f7f04fff97197c1ee5cb6.png?d=identicon&r=pg&s=64'},\n", " 'bio': 'Dr. Krysiak is an Instructor at the McDonnell Genome Institute at Washington University School of Medicine where she is involved in the comprehensive genomic analysis of cancer patient cohorts and “n-of-1” studies. She received her PhD in Molecular Genetics and Genomics at Washington University in St. Louis where she focused on the genetics of myelodysplastic syndrome through advanced flow cytometry techniques, primary cell culture and mouse models. She is a founding member of the CIViC team, helping to define the CIViC data model, and a leading content curator and feature development consultant.',\n", " 'created_at': '2015-02-26T04:14:20.953Z',\n", " 'display_name': 'kkrysiak',\n", " 'featured_expert': True,\n", " 'id': 6,\n", " 'last_seen_at': '2019-02-28T23:43:54.471Z',\n", " 'linkedin_profile': 'kilannin-krysiak-69047819',\n", " 'name': 'Kilannin Krysiak',\n", " 'orcid': '0000-0002-6299-9230',\n", " 'organization': {'description': 'The McDonnell Genome Institute (MGI) is a world leader in the fast-paced, constantly changing field of genomics. 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He has worked in genomics and bioinformatics since the earliest phase of reference genome sequencing. He contributed to the Mammalian Gene Collection, producing some of the first full-length sequences for many human genes. He also was part of a small team of bioinformaticians that helped sequence and release the first whole genome reference sequence for the severe acute respiratory syndrome (SARS) virus at the height of the 2003 epidemic. He has contributed to the identification of molecular markers at the DNA, RNA and protein level that are useful for diagnosis and prognosis of thyroid, breast, lymphoma and other cancers. His lab’s research is focused on the development of informatics resources and personalized medicine strategies for cancer using genomic technologies. He is a co-creator of the CIViC resource.',\n", " 'created_at': '2015-02-26T02:53:49.147Z',\n", " 'display_name': 'obigriffith',\n", " 'featured_expert': True,\n", " 'id': 3,\n", " 'last_seen_at': '2019-02-28T20:39:46.357Z',\n", " 'linkedin_profile': 'obigriffith',\n", " 'name': 'Obi Griffith',\n", " 'orcid': '0000-0002-0843-4271',\n", " 'organization': {'description': 'The McDonnell Genome Institute (MGI) is a world leader in the fast-paced, constantly changing field of genomics. A truly unique institution, we are pushing the limits of academic research by creating, testing, and implementing new approaches to the study of biology with the goal of understanding human health and disease, as well as evolution and the biology of other organisms.',\n", " 'id': 1,\n", " 'name': 'The McDonnell Genome Institute',\n", " 'profile_image': {'x128': '/system/organizations/profile_images/000/000/001/x128/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x14': '/system/organizations/profile_images/000/000/001/x14/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x256': '/system/organizations/profile_images/000/000/001/x256/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x32': '/system/organizations/profile_images/000/000/001/x32/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976',\n", " 'x64': '/system/organizations/profile_images/000/000/001/x64/MGI_STANDARD4_logo_brown-example_v1b.png?1494525976'},\n", " 'url': 'http://genome.wustl.edu/'},\n", " 'role': 'admin',\n", " 'twitter_handle': 'obigriffith',\n", " 'url': 'http://genome.wustl.edu/people/individual/obi-griffith/',\n", " 'username': 'obigriffith'}}},\n", " 'name': 'V600E',\n", " 'type': 'variant',\n", " 'variant_aliases': ['RS113488022', 'VAL600GLU'],\n", " 'variant_id': 12,\n", " 'variant_types': {'description': 'A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved.',\n", " 'display_name': 'Missense Variant',\n", " 'id': 47,\n", " 'name': 'missense_variant',\n", " 'so_id': 'SO:0001583',\n", " 'url': 'http://www.sequenceontology.org/browser/current_svn/term/SO:0001583'}}" ] }, "execution_count": 83, "metadata": {}, "output_type": "execute_result" } ], "source": [ "mv.getvariant('chr7:g.140453136A>T')['civic']['hgvs_expressions']\n" ] }, { "cell_type": "code", "execution_count": null, "metadata": { "collapsed": true }, "outputs": [], "source": [ "\n", "def get_evidence_statements(variant_ids, sample):\n", " evidence_statements = []\n", " \n", " sample_evidence_count = {}\n", " sample_evidence_count[sample] = [0,0,0,0]\n", " \n", " for item in variant_ids:\n", "\n", " for evidence in current_variant['evidence_items']:\n", "\n", " initial = str(gene) + ' ' +str(variant) + ' ' +evidence[0]['evidence_direction']+ ' ' + evidence[0]['clinical_significance']\n", " final = '(CIViC ' + evidence[0]['name'] + '- PMID:' + evidence[0]['source']['pubmed_id'] + ')'\n", "\n", " if evidence[0]['evidence_level'] != 'D' and evidence[0]['evidence_level'] != 'E':\n", "\n", " #PREDICTIVE\n", " if evidence[0]['evidence_type'] == 'Predictive':\n", " if evidence[0]['drug_interaction_type'] == 'Combination':\n", " drug_list = []\n", " for drug in evidence[0]['drugs']:\n", " drug_list.append(drug['name'])\n", " evidence_statements.append(initial + ' to ' + 'combination of ' + ', '.join(drug_list[:-1]) + ' and ' + str(drug_list[-1]) + ' for patients with ' + evidence[0]['disease'][ 'name'] + final)\n", "\n", " elif not evidence[0]['drug_interaction_type']:\n", " evidence_statements.append(initial + ' to ' + evidence[0]['drugs'][0]['name'] + ' for patients with ' + evidence[0]['disease'][ 'name'] + final)\n", "\n", " elif evidence[0]['drug_interaction_type'] == 'Substitutes':\n", " drug_list = []\n", " for drug in evidence[0]['drugs']:\n", " drug_list.append(drug['name'])\n", " evidence_statements.append(initial + ' to ' + ', '.join(drug_list[:-1]) + ' or ' + str(drug_list[-1]) + ' for patients with ' + evidence[0]['disease'][ 'name'] + final)\n", "\n", " elif evidence[0]['drug_interaction_type'] == 'Substitutes':\n", " drug_list = []\n", " for drug in evidence[0]['drugs']:\n", " drug_list.append(drug['name'])\n", " evidence_statements.append(initial + ' to ' + ', '.join(drug_list[:-1]) + ' or ' + str(drug_list[-1]) + ' for patients with ' + evidence[0]['disease'][ 'name'] + final)\n", "\n", " elif evidence[0]['drug_interaction_type'] == 'Sequential':\n", " drug_list = []\n", " for drug in evidence[0]['drugs']:\n", " drug_list.append(drug['name'])\n", " evidence_statements.append(initial + ' to ' + 'sequence of ' + ', '.join(drug_list[:-1]) + ' and ' + str(drug_list[-1]) + ' for patients with ' + evidence[0]['disease'][ 'name'] + final)\n", "\n", "\n", " #CREATE PROGNOSTIC EVIDENCE STATEMENT\n", " if evidence[0]['evidence_type'] == 'Prognostic':\n", " evidence_statements.append(initial + ' for patients with ' + evidence[0]['disease']['name'] + final)\n", "\n", "\n", " #CREATE DIAGNOSTIC EVIDENCE STATEMENT\n", " if evidence[0]['evidence_type'] == 'Diagnostic':\n", " evidence_statements.append(initial + ' for patients with ' + evidence[0]['disease']['name'] + final)\n", "\n", "\n", " #CREATE PREDISPOSING EVIDENCE STATEMENT\n", " if evidence[0]['evidence_type'] == 'Predisposing':\n", " evidence_statements.append(initial + ' Predisposition For Cancer ' + ' for patients with ' + evidence[0]['disease']['name'] + final)\n", "\n", " \n", " if evidence[0]['evidence_type'] == 'Predictive':\n", " sample_evidence_count[sample][0] += 1\n", " if evidence[0]['evidence_type'] == 'Prognostic':\n", " sample_evidence_count[sample][1] += 1\n", " if evidence[0]['evidence_type'] == 'Diagnostic':\n", " sample_evidence_count[sample][2] += 1\n", " if evidence[0]['evidence_type'] == 'Predisposing':\n", " sample_evidence_count[sample][3] += 1\n", " \n", " \n", " return evidence_statements, sample_evidence_count" ] }, { "cell_type": "code", "execution_count": 102, "metadata": {}, "outputs": [], "source": [ "processed = 0\n", "clinical_count = 0\n", "information = {}\n", "\n", "for i,row in somatic_variants.iterrows():\n", " processed +=1\n", " \n", " chrom = row['Chromosome']\n", " start = int(row['Start'])\n", " ref = row['Ref']\n", " var = row['Var']\n", " \n", " variant = myvariant.format_hgvs(chrom, start, ref, var)\n", " directory = mv.getvariant(variant)\n", " \n", " if directory:\n", " if 'civic' in directory.keys():\n", " clinical_correlates = {}\n", " clinical_count +=1\n", " gene = directory['civic']['entrez_name']\n", " varinat_type = directory['civic']['variant_types']['display_name']\n", " ENST = directory['cadd']['gene']['feature_id']\n", " ENSG = directory['cadd']['gene']['gene_id']\n", " protein_change = directory['civic']['name']\n", " pop_freq = directory['gnomad_exome']['af']['af']\n", " information[gene, varinat_type, ENSG, ENST, protein_change, pop_freq] = clinical_correlates\n", " \n", " \n", " \n", " " ] }, { "cell_type": "code", "execution_count": 103, "metadata": {}, "outputs": [ { "data": { "text/plain": [ "[['BRAF',\n", " 'Missense Variant',\n", " 'ENSG00000157764',\n", " 'ENST00000288602',\n", " 'V600E',\n", " 4.06458e-06]]" ] }, "execution_count": 103, "metadata": {}, "output_type": "execute_result" } ], "source": [ "information" ] }, { "cell_type": "code", "execution_count": 49, "metadata": {}, "outputs": [ { "ename": "IndentationError", "evalue": "expected an indented block (, line 41)", "output_type": "error", "traceback": [ "\u001b[0;36m File \u001b[0;32m\"\"\u001b[0;36m, line \u001b[0;32m41\u001b[0m\n\u001b[0;31m row_cells = table.add_row().cells\u001b[0m\n\u001b[0m ^\u001b[0m\n\u001b[0;31mIndentationError\u001b[0m\u001b[0;31m:\u001b[0m expected an indented block\n" ] } ], "source": [ "# def build_document(sample_name, input_list, CIViC_annotations):\n", "\n", "currentDT = datetime.datetime.now()\n", "\n", "document = Document()\n", "document.add_picture('Extra/report_header.png', width=Inches(6))\n", "document.add_heading('SOMATIC VARIANT ANNOTATION', 0)\n", "\n", "p = document.add_paragraph()\n", "p.add_run('Sample Name: ').bold = True\n", "p.add_run(str(sample_name) + '\\n')\n", "p.add_run('Date ').bold = True\n", "p.add_run(str(currentDT.strftime(\"%a, %b %d, %Y\")) + '\\n')\n", "p.add_run('Time Processed: ').bold = True\n", "p.add_run(str(currentDT.strftime(\"%I:%M:%S %p\")) + '\\n')\n", "p.add_run('Variants Processed: ').bold = True\n", "p.add_run(str(len(input_list)) + '\\n')\n", "p.add_run('Clinical Annotations: ').bold = True\n", "p.add_run(str(len(input_list)) + '\\n')\n", "\n", "document.add_heading('Direct CIViC Annotations' + '\\n', level=1) \n", "\n", "\n", "for item in information:\n", " \n", " \n", " \n", " \n", " \n", " \n", " \n", " table = document.add_table(rows=1, cols=5, style = 'Table Grid')\n", " table = document.add_table(rows=1, cols=5, style = 'Table Grid')\n", " table.allow_autofit= True\n", " hdr_cells = table.rows[0].cells\n", " run = hdr_cells[0].paragraphs[0].add_run('Gene')\n", " run.bold = True\n", " run = hdr_cells[1].paragraphs[0].add_run('Variant')\n", " run.bold = True\n", " run = hdr_cells[2].paragraphs[0].add_run('Description')\n", " run.bold = True\n", " run = hdr_cells[3].paragraphs[0].add_run('CIViC EID')\n", " run.bold = True\n", " run = hdr_cells[4].paragraphs[0].add_run('PubMedID')\n", " run.bold = True\n", "\n", "for i, row in CIViC_annotation.iterrows():\n", " row_cells = table.add_row().cells\n", " row_cells[0].text = row['Gene']\n", " row_cells[1].text = row['Variant']\n", " row_cells[2].text = row['Description']\n", " row_cells[3].text = row['CIViC Link']\n", " row_cells[4].text = row['PubMedID Link']\n", "\n", " \n", "p = document.add_paragraph('\\n' + 'OpenCAP is intended for research use only and clinical applications of subsequent panels designed using the SOP would require further panel validation.')\n", "\n", "document.save('demo.docx')" ] }, { "cell_type": "code", "execution_count": null, "metadata": { "collapsed": true }, "outputs": [], "source": [] } ], "metadata": { "kernelspec": { "display_name": "Python 3", "language": "python", "name": "python3" }, "language_info": { "codemirror_mode": { "name": "ipython", "version": 3 }, "file_extension": ".py", "mimetype": "text/x-python", "name": "python", "nbconvert_exporter": "python", "pygments_lexer": "ipython3", "version": "3.6.1" } }, "nbformat": 4, "nbformat_minor": 2 }