Molecular Alterations in Patients of Color with Advanced Cutaneous and Unknown Primary Melanomas.

BACKGROUND: Cutaneous melanoma is rare in Patients of Color (POC), and the genomics are not well understood. OBJECTIVE: Describe MAPK drivers and tumor mutational burden (TMB) of cutaneous and unknown primary (CUP) melanoma in POC and compare them to non-Hispanic White (NHW) patients. METHODS: We analyzed a retrospective convenience cohort of 676 patients with advanced CUP melanoma undergoing clinically-warranted multigene sequencing with MSK-IMPACT. Self-identified (self-ID) POC were defined as non-White race and/or Hispanic ethnicity; this cohort was also analyzed by genetically inferred ancestry and skin tone using Monk scale. RESULTS: Self-ID POC (n=35) had frequent BRAF V600E mutations (43%) and, compared to NHW (N=641) patients, more "pan-wildtype" tumors of unknown driver (14% vs 4%, p=0.010). Among self-ID POC, skin tone and inferred ancestry showed moderate overlap, but did not consistently predict genomic features. Median TMB was higher for patients with light (N=185) vs medium/dark (N=8) skin tone (15.8 vs 2.6, p<0.0001). LIMITATIONS: Skin tone assessments were only available for a subset of patients (N=193). BRAF mutations are underestimated given molecular testing preferentially sent in patients with BRAF-wildtype disease. CONCLUSION: CUP melanomas in self-ID POC had lower median TMB and were more likely to be pan-wildtype, reflecting differences in pathogenesis. Larger scale studies are needed to validate these findings.