TERT promoter mutations are associated with longer progression-free and overall survival in patients with BRAF-mutant melanoma receiving BRAF and MEK inhibitor therapy

Carl M. Thielmann*, Johanna Matull, Anne Zaremba, Rajmohan Murali, Eleftheria Chorti, Georg Lodde, Philipp Jansen, Rudolf Herbst, Patrick Terheyden, Jochen Utikal, Claudia Pföhler, Jens Ulrich, Alexander Kreuter, Peter Mohr, Ralf Gutzmer, Friedegund Meier, Edgar Dippel, Michael Weichenthal, Julia Kretz, Inga MöllerAntje Sucker, Annette Paschen, Elisabeth Livingstone, Lisa Zimmer, Eva Hadaschik, Selma Ugurel, Dirk Schadendorf, Klaus G. Griewank*

*Corresponding author for this work
8 Citations (Scopus)

Abstract

Background: Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF-targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting. Methods: The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan–Meier and univariate/multivariate Cox regression analyses were performed as appropriate. Results: median age at first diagnosis was 54 years (range 16–84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [N = 87] vs 5.0 months [N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33–0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32–0.70]) as well as the validation cohort (mPFS of 7.3 months [N = 80] vs 5.8 months [N = 32]; HR = 0.67 [95%CI 0.41–1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18–0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45–0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35–0.75, P = 0.0001). Conclusions: In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma.

Original languageEnglish
JournalEuropean Journal of Cancer
Volume161
Pages (from-to)99-107
Number of pages9
ISSN0959-8049
DOIs
Publication statusPublished - 01.2022

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