BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

Abstract

The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of 3 Italian Melanoma Intergroup centers. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation (CNV) was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. Overall, 107 MMPs were included in the study. The VAF cutoff determined by ROC curve was 41.3%. At multivariate analysis, progression free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p<0.01)], in those with VAF >41.3% [(HR 1.62 (95% CI 1.04-2.54, p<0.05)], and in those with ECOG PS ≥1 [(HR 1.82 (95% CI 1.15-2.88, p<0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [(HR 2.01 (95% CI 1.25-3.25, p<0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% (HR 1.46 (95% CI 0.93-2.29, p=0.06), and in patients with ECOG PS ≥1 [(HR 1.52 (95% CI 0.94-2.87, p=0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7-11% of patients.