<i>BRAF</i> Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors

Abstract

Metastatic melanoma is characterized by complex genomic alterations, including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in <i>BRAF</i>-mutant melanoma, inducing a mutant allele-specific imbalance. Although <i>BRAF</i> amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if <i>BRAF</i> copy-number variation and <i>BRAF</i> mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess <i>BRAF</i> copy number and mutant allele frequency in pretreatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy, and we analyzed the association with progression-free survival. We found that 65% patients displayed <i>BRAF</i> gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced <i>BRAF</i>-mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high <i>BRAF</i> mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid <i>BRAF</i> status versus those with <i>BRAF</i> gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; <i>P</i> = 0.01] and in patients with low percentage versus those with a balanced <i>BRAF</i> mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; <i>P</i> = 0.016). Our data suggest that quantitative analysis of the <i>BRAF</i> gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. <i>Mol Cancer Ther; 17(6); 1332-40. ©2018 AACR</i>.