Human Cancer Biology Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma

Purpose:Certain clinicopathologic features correlate with BRAFmutation status inmelanoma including younger age and primary subtype. This study sought to determine the BRAFmutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma. Methods: A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N1⁄4 308). Clinicopathologic variables were correlated with BRAFmutational status, genotype, and survival. Results: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAFmutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% 70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. NonV600E genotypes comprised <20% in patients <50 years and >40% in those 70 years. A higher degree of cumulative sun-induced damage correlatedwith V600K but not V600Emelanoma (P1⁄4 0.002). The diseasefree interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P 1⁄4 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001). Conclusion: Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. Clin Cancer Res; 18(12);