Treatment selection for advanced melanoma, particularly for patients with BRAF V600 mutations who may be eligible for either immune checkpoint inhibitors (ICI) or targeted BRAF/MEK inhibitor combinations, remains an area of active debate. Additional molecular biomarkers are needed to improve therapeutic choice. Mutations in the telomerase reverse transcriptase (TERT) promoter are common in melanoma, yet their clinical relevance in the modern treatment era is not well established. This retrospective single-center study set out to assess the prevalence of TERT promoter mutations and their association with clinical outcomes in metastatic melanoma patients treated with first-line ICI or BRAF/MEK inhibitors.
The authors performed a retrospective analysis including patients with metastatic melanoma who received first-line systemic therapy with either immune checkpoint inhibitors or BRAF/MEK inhibitors. Tumor samples were analyzed with a customized next-generation sequencing panel to determine TERT promoter mutational status and to identify co-occurring mutations. Survival outcomes evaluated were overall survival (OS) and progression-free survival (PFS). The Kaplan-Meier method was used for survival estimates and the log-rank test to compare groups. Multivariable analyses were undertaken to account for potential confounders where applicable.
A total of 159 patients with metastatic melanoma were included. Molecular profiling by the customized NGS panel identified presence or absence of TERT promoter mutations and cataloged co-mutations, including BRAF V600 alterations. The study population included patients eligible for first-line ICI or targeted therapy according to their disease characteristics and mutation profile. Specific demographic details, treatment regimens, and exact panel composition were reported in the original paper but are summarized here only in the context of the study design and main findings.
TERT promoter mutations were detected in 73% of the cohort, indicating a high prevalence among patients with metastatic melanoma in this series. Among cases harboring TERT promoter mutations, co-occurrence with BRAF V600 mutations was frequent, observed in 84% of TERT-mutant tumors. These findings confirm that TERT promoter alterations are common and often coexist with canonical driver mutations in melanoma.
In the overall study population, TERT mutational status alone was not associated with differences in OS or PFS. Instead, clinical features including presence of brain metastases, liver metastases, elevated lactate dehydrogenase (LDH) levels, and higher metastatic burden emerged as the principal determinants of outcome. These variables retained importance in multivariable assessment and were stronger predictors of survival than TERT status in this cohort.
Within the subgroup of patients carrying BRAF V600 mutations, exploratory analyses examined potential interactions between TERT promoter status and first-line treatment modality. In this subgroup, patients with co-occurring BRAF/TERT mutations experienced longer median OS when treated with ICI compared with those treated with BRAF/MEK inhibitors (reported medians: 50.3 months vs 14.6 months). Conversely, patients with TERT wild-type tumors showed an opposite trend, with longer median OS on BRAF/MEK inhibitors compared with ICI (reported medians: 20.9 months vs 7.8 months). Similar directional patterns were observed for PFS.
However, these subgroup results were derived from small patient numbers and were not consistently confirmed by multivariable modeling. The authors characterize these observations as exploratory and hypothesis-generating rather than definitive evidence of a predictive interaction.
The study documents a high prevalence of TERT promoter mutations in metastatic melanoma and frequent co-occurrence with BRAF V600 alterations. Despite this, TERT status did not independently predict OS or PFS across the entire cohort. Clinical stage and disease distribution (brain/liver metastases), LDH, and tumor burden remained dominant prognostic factors.
Exploratory subgroup analyses suggest a potential differential benefit of ICI versus targeted BRAF/MEK therapy according to TERT status in BRAF V600-mutant patients. Specifically, the data raise the hypothesis that co-occurring TERT promoter mutations might favor better outcomes with ICI relative to targeted therapy, while TERT wild-type cases might fare better with targeted agents. The authors caution that these signals are preliminary.
Key limitations include the retrospective, single-center design and the small sample sizes for the treatment-by-TERT subgroup comparisons. These limitations reduce the ability to draw causal inferences or to generalize the subgroup observations. Details required to fully evaluate potential confounding and the statistical robustness of multivariable models are contained in the full article. The authors recommend prospective, well-designed studies to validate any predictive role of TERT promoter mutations and to investigate underlying biological mechanisms that could explain treatment-specific interactions.
In this retrospective cohort of 159 patients with metastatic melanoma, TERT promoter mutations were common and often co-occurred with BRAF V600 mutations, but TERT status was not independently associated with OS or PFS in the overall population. Exploratory analyses suggest a possible interaction between TERT promoter status and the choice of first-line therapy in BRAF V600-mutant patients; however, these findings are preliminary and require validation in prospective trials before they can influence clinical practice.