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Clin Cancer Res. 2017 Sep 1;23(17):5238-5245. doi: 10.1158/1078-0432.CCR-17-0172. Epub 2017 May 23.

Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.

Author information

1
Genentech, Inc., South San Francisco, California. wongchenko.matthew@gene.com.
2
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and University of Melbourne, Parkville, Victoria, Australia.
3
Nantes University, Nantes, France.
4
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
5
Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.
6
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
7
HistoGeneX, Antwerp, Belgium.
8
Genentech, Inc., South San Francisco, California.
9
Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, California.

Abstract

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-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.

PMID:
28536307
DOI:
10.1158/1078-0432.CCR-17-0172
[Indexed for MEDLINE]
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