Gene Expression Profiling inBRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
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Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients withBRAFV600-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.Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.
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Clin Cancer Res, 2017, 23 (17), pp. 5238 - 5245