Association Between pTERT Promoter Mutation Subtypes and Survival Outcomes in BRAF ‐Mutant Metastatic Melanoma Treated With BRAF / MEK Inhibitors: An Exploratory Study

BACKGROUND: The use of targeted therapies, such as BRAF/MEK inhibitors, has led to a considerable increase in melanoma-specific survival rates; however, prolonged responses remain uneven and uncertain. Moreover, there is a lack of reliable biomarkers that can predict the type and duration of the response. This study aimed to determine whether pTERT mutations affect progression-free survival and overall survival in melanoma patients treated with BRAF/MEK inhibitors. MATERIALS AND METHODS: This study employed a retrospective observational design. We included 77 patients with metastatic BRAF (V600) mutated melanoma treated with BRAF/MEK inhibitors. The data analysis included only patients with known pTERT mutation status (WT, -124C>T, -146C>T, and -138_139 CC>TT) and clinical variables collected at two different centers. Progression-free survival and overall survival were determined using Kaplan-Meier curves and Cox regression models. RESULTS: A multivariate analysis with 56-month follow-up suggested a decreased melanoma overall survival with BRAF (V600K) mutation (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.2-4.0; p = 0.016), the Stage M1c/M1d (HR 3.3; 95% CI 1.7-6.5; p = 0.001), ECOG ≥ 1 (HR 3.6; 95% CI 1.9-6.7; p = 0.001) and not having the -138_139 CC>TT pTERT mutation (HR 3.2; 95% CI 1.0-10.5; p = 0.052). CONCLUSION: These findings suggest that the tandem -138_139 CC>TT, a less frequent pTERT mutation subtype, may be associated with a trend toward improved prognosis in patients with metastatic melanoma treated with BRAF/MEK inhibitors. However, due to the limited sample size, this study is essentially an exploratory investigation. It requires independent validation with a larger sample to determine the effect of TERT promoter mutations, together with other clinical parameters, on treatment response to BRAF/MEK inhibitors.