Concordance of somatic mutation profiles (BRAF, NRAS, and TERT) and tumoral PD-L1 in matched primary cutaneous and metastatic melanoma samples

Shi Yang, Dominick A Leone, Asok Biswas, April Deng, Drazen Jukic, Rajendra Singh, Uma Sundram, Meera Mahalingam

Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/ NRAS/TERT and, immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and, direct-DNA Sanger sequencing for BRAF/ NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen's kappa (ĸ). Poor concordance among primary and corresponding metastases were noted in: BRAF (9/42 cases discordant, ĸ=0.49, 95%CI: 0.21-0.77, P=.0013), TERT promoter mutations (13/41 cases discordant, ĸ=0.33, 95%CI: 0.04-0.62, P=.033), tumoral PD-L1 immunoexpression (9/43 cases discordant, ĸ=0.39, 95%CI: 0.07-0.72, P=.0099) and immunoexpression of CD8+ T lymphocytes (12/43 cases discordant, ĸ=0.44, 95%CI: 0.19-0.69, P=.002). While NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 vs. 455days for pairs with concordant status (P=.07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma.