Prognostic and Clinicopathologic Associations of Oncogenic <i>BRAF</i> in Metastatic Melanoma

TLDR

The study aimed to determine the prevalence and types of oncogenic BRAF mutations in metastatic melanoma and examine their association with clinicopathologic characteristics and patient outcomes. The authors prospectively evaluated 197 Australian metastatic melanoma patients, assessed BRAF mutation status, correlated a wide array of clinicopathologic variables, and performed survival analysis. Forty‑eight percent of patients carried BRAF mutations (mostly V600E), with no major differences in metastatic clinicopathologic features except younger age at distant metastasis, while survival was shorter for untreated BRAF‑mutant patients (5.7 months) compared to BRAF‑wild‑type (8.5 months) and was not reached for BRAF‑mutant patients receiving BRAF inhibitors.

Abstract

To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.