Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.

6533b7d6fe1ef96bd1265ba2

RESEARCH PRODUCT

Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.

Fei Ye Willy Hugo Dirk Schadendorf Zeynep Eroglu Antoni Ribas Jürgen C. Becker Xiangju Kong Richard F. Kefford Simone M. Goldinger Alexander M. Menzies Antje Sucker Carmen Loquai John F. Thompson John F. Thompson Gulietta M. Pupo Helen Rizos Ralf Gutzmer Jeffrey A. Sosman Levi A. Garraway Shilin Zhao Douglas B. Johnson Carola Berking Richard A. Scolyer Friederike Egberts Roger S. Lo Helen Gogas Lisa Zimmer Georgina V. Long

subject

Oncology Neuroblastoma RAS viral oncogene homolog Male Cancer Research Skin Neoplasms Time Factors Resistance DNA Mutational Analysis Drug Resistance Medizin Kaplan-Meier Estimate Bioinformatics medicine.disease_cause Risk Factors 2.1 Biological and endogenous factors Aetiology Vemurafenib Melanoma Cancer Mutation Tumor Dabrafenib Melanoma Acquired Middle Aged Phenotype Europe Phenotype Treatment Outcome Splice Oncology Meta-analysis Public Health and Health Services Disease Progression Female medicine.drug Signal Transduction Proto-Oncogene Proteins B-raf medicine.medical_specialty Oncology and Carcinogenesis NRAS Antineoplastic Agents Biology Disease-Free Survival Article BRAF MEK1 Clinical Research Internal medicine Genetics medicine Biomarkers Tumor Humans Genetic Predisposition to Disease Oncology & Carcinogenesis Protein Kinase Inhibitors Proportional Hazards Models Proportional hazards model Australia Dabrafenib medicine.disease MAPK United States Meta-analysis Vemurafenib Drug Resistance Neoplasm Mutation Neoplasm Biomarkers

description

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms.ConclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.

year	journal	country	edition	language
2015-12-01	European journal of cancer (Oxford, England : 1990)

10.1016/j.ejca.2015.08.022 https://pubmed.ncbi.nlm.nih.gov/26608120