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

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

doi:10.1016/j.ejca.2015.08.022

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

Eur J Cancer. 2015 Dec;51(18):2792-9. doi: 10.1016/j.ejca.2015.08.022. Epub 2015 Nov 19.

Authors

Douglas B Johnson¹, Alexander M Menzies², Lisa Zimmer³, Zeynep Eroglu⁴, Fei Ye⁵, Shilin Zhao⁵, Helen Rizos⁶, Antje Sucker³, Richard A Scolyer⁷, Ralf Gutzmer⁸, Helen Gogas⁹, Richard F Kefford¹⁰, John F Thompson⁷, Jürgen C Becker¹¹, Carola Berking¹², Friederike Egberts¹³, Carmen Loquai¹⁴, Simone M Goldinger¹⁵, Gulietta M Pupo¹⁶, Willy Hugo¹⁷, Xiangju Kong¹⁷, Levi A Garraway¹⁸, Jeffrey A Sosman⁵, Antoni Ribas¹⁷, Roger S Lo¹⁷, Georgina V Long², Dirk Schadendorf³

Affiliations

¹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: douglas.b.johnson@vanderbilt.edu.
² 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.
³ Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
⁴ 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.
⁵ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Macquarie University, Sydney, NSW, Australia.
⁷ Melanoma Institute Australia, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
⁸ Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
⁹ First Department of Medicine, University of Athens Medical School, Athens, Greece.
¹⁰ 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.
¹¹ Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
¹² Department of Dermatology, Ludwig-Maximilians-University, Munich, Germany.
¹³ Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Dermatology, University Medical Center, Mainz, Germany.
¹⁵ Department of Dermatology, University Hospital Zürich, Switzerland.
¹⁶ Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia.
¹⁷ Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

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.

Keywords: Acquired; BRAF; Dabrafenib; MAPK; MEK1; Meta-analysis; NRAS; Resistance; Splice; Vemurafenib.

Publication types

Meta-Analysis
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use*
Australia
Biomarkers, Tumor / antagonists & inhibitors*
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
DNA Mutational Analysis
Disease Progression
Disease-Free Survival
Drug Resistance, Neoplasm* / genetics
Europe
Female
Genetic Predisposition to Disease
Humans
Kaplan-Meier Estimate
Male
Melanoma / drug therapy*
Melanoma / enzymology
Melanoma / genetics
Melanoma / mortality
Melanoma / pathology
Middle Aged
Mutation
Phenotype
Proportional Hazards Models
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Risk Factors
Signal Transduction / drug effects
Skin Neoplasms / drug therapy*
Skin Neoplasms / enzymology
Skin Neoplasms / genetics
Skin Neoplasms / mortality
Skin Neoplasms / pathology
Time Factors
Treatment Outcome
United States

Substances

Antineoplastic Agents
Biomarkers, Tumor
Protein Kinase Inhibitors
BRAF protein, human
Proto-Oncogene Proteins B-raf

Abstract

Publication types

MeSH terms

Substances

Grants and funding