Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors.

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 -mutant melanoma, inducing a mutant allele-specific imbalance. Although amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if copy-number variation and mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess 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 gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced -mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid status versus those with gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; = 0.01] and in patients with low percentage versus those with a balanced mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; = 0.016). Our data suggest that quantitative analysis of the gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. .