Abstract
Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma. A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival. Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation 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. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those ≥ 70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free 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 = 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). Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior.
Highlights
The recent characterization of molecular subtypes of melanoma [1, 2] has led to the rapid clinical application of highly active and potent inhibitors of oncogenic mutated BRAF and CKIT proteins in patients with metastatic melanoma [3, 4]
Primary melanoma and BRAF genotype BRAF-mutant metastatic melanoma was significantly associated with superficial spreading and nodular primary melanoma histogenetic subtypes (P < 0.001) and not associated with mucosal or acral primary melanoma types (P 1⁄4 0.048) when compared with wild-type disease
Median overall survival (OS) from date of diagnosis of metastatic melanoma was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (45.2 months) than patients with BRAFmutant melanoma not treated with an inhibitor
Summary
The recent characterization of molecular subtypes of melanoma [1, 2] has led to the rapid clinical application of highly active and potent inhibitors of oncogenic mutated BRAF and CKIT proteins in patients with metastatic melanoma [3, 4]. Vemurafenib has showed an overall survival (OS) benefit over dacarbazine in patients with BRAF-mutant (V600E) metastatic melanoma [11]. Ninety-five percent of BRAF mutations occur at V600 (single amino acid substitution at valine 600) and constitutively activate this oncogene [14]. The most common genotype is V600E (valine to glutamic acid), with early reports suggesting this accounts for up to 95% of BRAF-mutant melanoma [1]. Large studies recently conducted in Australia [13], Texas [15], and Florida [16] show that the V600E genotype is not as prevalent, and that V600K (valine to lysine), may comprise 20% or more of BRAFmutant melanomas
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