Dissecting the Spectrum of Rare BRAF Mutations in Melanoma: A Nation-Wide Study by the Italian Melanoma Intergroup (IMI)

: Non-V600E/K BRAF mutations have been reported in melanoma, but data on their clinical relevance are conflicting. This study investigated the distribution, prognostic role, and functional impact of rare BRAF mutations in melanoma. We retrospectively assessed frequency, response to therapy and outcome of rare BRAF mutations compared to V600E/K in cases from 19 Italian Melanoma group (IMI) centers. 258/14,081 samples (1.8%) harbored rare BRAF mutations, 40% encompassing codon 600. Overall and progression-free survival (OS, PFS) following target therapy with BRAF/MEK inhibitors were comparable to V600E/K mutant melanoma (HR = 0.85 and 0.89, p > 0.1). Response to target therapy was lower, albeit not significantly, in rare BRAF mutant melanomas compared to V600E/K (48% vs. 66%, p > 0.05). OS, PFS, and objective response in cases treated with immunotherapy were unaffected by BRAF status. Molecular dynamics simulation assessing whether selected BRAF variants affected BRAF structure similarly to V600E showed variable degrees of destabilization towards constitutive protein activation, particularly for mutations encompassing codons 599-601. These results indicate that rare BRAF mutations can modify BRAF kinase activity including a subset of mutations outside but close to codon 600. Molecular approaches able to detect rare BRAF mutations could identify additional melanoma cases eligible for therapies with BRAF/MEK inhibitors.