Exploring the Role of TERT Promoter Mutations in Advanced Melanoma Treated With BRAF/MEK Inhibitors or Immune Checkpoint Inhibitors

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Background/Aim: Advanced melanoma treatment remains debated, particularly in patients with B-Raf proto-oncogene serine/threonine kinase (BRAF) V600 mutations eligible for both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Additional biomarkers are needed to improve treatment selection. Mutations of the telomerase reverse transcriptase (TERT) promoter are frequent in melanoma, although their clinical role remains unclear. Patients and Methods: We conducted a retrospective single-center study including patients with metastatic melanoma treated with first-line ICI or BRAF/MEK inhibitors. TERT mutational status and co-mutations were assessed using a customized next-generation sequencing panel. Overall (OS) and progression-free (PFS) survival were estimated using the Kaplan-Meier method and compared with the log-rank test. Results: Among 159 patients, TERT mutations were detected in 73% of cases and frequently co-occurred with BRAFV600 mutations (84%). In the overall population, TERT status was not associated with OS or PFS. Brain and liver metastases, lactate dehydrogenase levels, and metastatic burden were the main determinants of outcome. In the BRAFV600-mutant subgroup, exploratory analyses suggested a potential interaction between TERT status and the agents used in first-line treatment. Patients with BRAF/TERT co-mutations showed longer OS when treated with ICI than with BRAF/MEK inhibitors (50.3 vs. 14.6 months), whereas the opposite trend was observed in patients with wild-type TERT (7.8 vs. 20.9 months). Similar patterns were observed for PFS, although findings were based on small subgroups and not consistently supported by multivariable analyses. Conclusion: TERT promoter mutations were not independently associated with survival outcomes in metastatic melanoma. Although exploratory findings suggest a possible interaction between TERT status and treatment type, further investigation of its biological relevance in well-designed prospective studies are needed.

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