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Cited by 323

The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.

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

Open access
Johnson, Douglas B., Menzies, Alexander M., Zimmer, Lisa, Eroglu, Zeynep, Ye, Fei, Zhao, Shilin, Rizos, Helen, Sucker, Antje, Scolyer, Richard A., Gutzmer, Ralf, Gogas, Helen, Kefford, Richard F., Thompson, John F., Becker, Jürgen C., Berking, Carola, Egberts, Friederike, Loquai, Carmen, Goldinger, Simone M., Pupo, Gulietta M., Hugo, Willy, Kong, Xiangju, Garraway, Levi A., Sosman, Jeffrey A., Ribas, Antoni, Lo, Roger S., Long, Georgina V., Schadendorf, Dirk·2015·European Journal of Cancer
DOI 10.1016/j.ejca.2015.08.022
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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 PCR-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-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with >1 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 characterize 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.

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Metadata

Authors
Johnson, D. B., Menzies, A. M., Zimmer, L., Eroglu, Z., Ye, F., Zhao, S., Rizos, H., Sucker, A., Scolyer, R. A., Gutzmer, R., Gogas, H., Kefford, R. F., Thompson, J. F., Becker, J. C., Berking, C., Egberts, F., Loquai, C., Goldinger, S. M., Pupo, G. M., Hugo, W., Kong, X., Garraway, L. A., Sosman, J. A., Ribas, A., Lo, R. S., Long, G. V., & Schadendorf, D.
Venue
European Journal of Cancer
Publisher
Elsevier BV
Published
2015-12
Volume
51
Issue
18
Pages
2792-2799
ISSN
0959-8049 (ISSN-L)
DOI
10.1016/j.ejca.2015.08.022
OpenAlex
W2176310149
Cited by
323
References
34
FWCI
2.31
Type
journal article
Language
en
Open access
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