TY - JOUR
T1 - Gene expression profiling in BRAF-mutated melanoma reveals patient subgroups with poor outcomes to vemurafenib that may be overcome by cobimetinib plus vemurafenib
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
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/9/1
Y1 - 2017/9/1
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-17-0172
DO - 10.1158/1078-0432.CCR-17-0172
M3 - Article
C2 - 28536307
AN - SCOPUS:85029484941
SN - 1078-0432
VL - 23
SP - 5238
EP - 5245
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -