Abstract
<div>AbstractPurpose:<p><i>BRAF</i> V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to <i>BRAFi</i>±<i>MEKi</i>. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy.</p>Experimental Design:<p>Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with <i>BRAFi</i>±<i>MEKi</i> underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined.</p>Results:<p>Baseline tissue and clinical outcome with <i>BRAFi</i>±<i>MEKi</i> were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, <i>P</i> = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, <i>P</i> = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in <i>PIK3R1</i> and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (<i>n</i> = 19) had superior outcomes than V600E (<i>n</i> = 84), including response rate (53% vs. 29%, <i>P</i> = 0.059), PFS (median, 19 vs. 2.7 months, <i>P</i> = 0.049), and overall survival (20.4 vs. 11.7 months, <i>P</i> = 0.081).</p>Conclusions:<p><i>BRAF</i> V600K melanomas appear to benefit less from <i>BRAFi</i>±<i>MEKi</i> than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.</p></div>
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