Gene expression profiling in BRAF-mutated melanoma reveals patient subgroups with poor outcomes to vemurafenib that may be overcome by cobimetinib plus vemurafenib

Matthew J. Wongchenko, Grant A. McArthur, Brigitte Dreno, James Larkin, Paolo A. Ascierto, Jeffrey Sosman, Luc Andries, Mark Kockx, Stephen D. Hurst, Ivor Caro, Isabelle Rooney, Priti S. Hegde, Luciana Molinero, Huibin Yue, Ilsung Chang, Lukas Amler, Yibing Yan, Antoni Ribas

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Abstract

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF V600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature.

Original languageEnglish
Pages (from-to)5238-5245
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number17
DOIs
Publication statusPublished - Sep 1 2017

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Gene Expression Profiling
Melanoma
Disease-Free Survival
Cell Cycle
Confidence Intervals
Genes
cdc Genes
GDC-0973
PLX4032
Principal Component Analysis
Transcriptome
Cluster Analysis
Neoplasms
Research Design
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Gene expression profiling in BRAF-mutated melanoma reveals patient subgroups with poor outcomes to vemurafenib that may be overcome by cobimetinib plus vemurafenib. / Wongchenko, Matthew J.; McArthur, Grant A.; Dreno, Brigitte; Larkin, James; Ascierto, Paolo A.; Sosman, Jeffrey; Andries, Luc; Kockx, Mark; Hurst, Stephen D.; Caro, Ivor; Rooney, Isabelle; Hegde, Priti S.; Molinero, Luciana; Yue, Huibin; Chang, Ilsung; Amler, Lukas; Yan, Yibing; Ribas, Antoni.

In: Clinical Cancer Research, Vol. 23, No. 17, 01.09.2017, p. 5238-5245.

Research output: Contribution to journalArticle

Wongchenko, MJ, McArthur, GA, Dreno, B, Larkin, J, Ascierto, PA, Sosman, J, Andries, L, Kockx, M, Hurst, SD, Caro, I, Rooney, I, Hegde, PS, Molinero, L, Yue, H, Chang, I, Amler, L, Yan, Y & Ribas, A 2017, 'Gene expression profiling in BRAF-mutated melanoma reveals patient subgroups with poor outcomes to vemurafenib that may be overcome by cobimetinib plus vemurafenib', Clinical Cancer Research, vol. 23, no. 17, pp. 5238-5245. https://doi.org/10.1158/1078-0432.CCR-17-0172
Wongchenko, Matthew J. ; McArthur, Grant A. ; Dreno, Brigitte ; Larkin, James ; Ascierto, Paolo A. ; Sosman, Jeffrey ; Andries, Luc ; Kockx, Mark ; Hurst, Stephen D. ; Caro, Ivor ; Rooney, Isabelle ; Hegde, Priti S. ; Molinero, Luciana ; Yue, Huibin ; Chang, Ilsung ; Amler, Lukas ; Yan, Yibing ; Ribas, Antoni. / Gene expression profiling in BRAF-mutated melanoma reveals patient subgroups with poor outcomes to vemurafenib that may be overcome by cobimetinib plus vemurafenib. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 17. pp. 5238-5245.
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abstract = "Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF V600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95{\%} confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95{\%} CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95{\%} CI, 0.7-1.8; P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature.",
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AU - Wongchenko, Matthew J.

AU - McArthur, Grant A.

AU - Dreno, Brigitte

AU - Larkin, James

AU - Ascierto, Paolo A.

AU - Sosman, Jeffrey

AU - Andries, Luc

AU - Kockx, Mark

AU - Hurst, Stephen D.

AU - Caro, Ivor

AU - Rooney, Isabelle

AU - Hegde, Priti S.

AU - Molinero, Luciana

AU - Yue, Huibin

AU - Chang, Ilsung

AU - Amler, Lukas

AU - Yan, Yibing

AU - Ribas, Antoni

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N2 - Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF V600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature.

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