TY - JOUR
T1 - Acquired BRAF inhibitor resistance
T2 - a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms
AU - Johnson, Douglas B.
AU - Menzies, Alexander M.
AU - Zimmer, Lisa
AU - Eroglu, Zeynep
AU - Ye, Fei
AU - Zhao, Shilin
AU - Rizos, Helen
AU - Sucker, Antje
AU - Scolyer, Richard A.
AU - Gutzmer, Ralf
AU - Gogas, Helen
AU - Kefford, Richard F.
AU - Thompson, John F.
AU - Becker, Jürgen C.
AU - Berking, Carola
AU - Egberts, Friederike
AU - Loquai, Carmen
AU - Goldinger, Simone M.
AU - Pupo, Gulietta M.
AU - Hugo, Willy
AU - Kong, Xiangju
AU - Garraway, Levi A.
AU - Sosman, Jeffrey A.
AU - Ribas, Antoni
AU - Lo, Roger S.
AU - Long, Georgina V.
AU - Schadendorf, Dirk
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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%), BRAFV600E/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.
AB - 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%), BRAFV600E/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.
UR - http://www.scopus.com/inward/record.url?scp=84959536816&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2015.08.022
DO - 10.1016/j.ejca.2015.08.022
M3 - Article
C2 - 26608120
AN - SCOPUS:84959536816
SN - 0959-8049
VL - 51
SP - 2792
EP - 2799
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 18
ER -