title: Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.
abstract: BACKGROUND
  Acquired 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Among 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: douglas.b.johnson@vanderbilt.edu.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Eroglu
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Macquarie University, Sydney, NSW, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: First Department of Medicine, University of Athens Medical School, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Macquarie University, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Dermatology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.affiliation: Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Egberts
authors.affiliation: Department of Dermatology, University Medical Center, Mainz, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Department of Dermatology, University Hospital Zürich, Switzerland.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia.
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001315:Australia; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Acquired; BRAF; Dabrafenib; MAPK; MEK1; Meta-analysis; NRAS; Resistance; Splice; Vemurafenib