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

Autor: Thielmann CM; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany. Electronic address: carlmaximilian.thielmann@uk-essen.de., Matull J; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Zaremba A; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Murali R; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA., Chorti E; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Lodde G; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Jansen P; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Herbst R; Skin Cancer Unit, Helios Klinikum Erfurt, Erfurt, Germany., Terheyden P; Department of Dermatology, UKSH Campus Lübeck, Lübeck, Germany., Utikal J; Skin Cancer Unit, German Cancer Research Center (DKFZ), Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany., Pföhler C; Department of Dermatology, Saarland University Medical School, Homburg, Saar, Germany., Ulrich J; Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany., Kreuter A; Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Klinik Oberhausen, University Witten/Herdecke, Oberhausen, Germany., Mohr P; Dermatological Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany., Gutzmer R; Skin Cancer Center, Hannover Medical School, Hannover, Germany; Department of Dermatology, Mühlenkreiskliniken Minden, Minden, Germany., Meier F; Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany., Dippel E; Department of Dermatology Ludwigshafen, Klinikum der Stadt Ludwigshafen Am Rhein GGmbH, Ludwigshafen, Germany., Weichenthal M; Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany., Kretz J; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Möller I; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Sucker A; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Paschen A; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Livingstone E; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Zimmer L; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Hadaschik E; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Ugurel S; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Schadendorf D; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany., Griewank KG; Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany. Electronic address: klaus.griewank@uk-essen.de.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2022 Jan; Vol. 161, pp. 99-107. Date of Electronic Publication: 2021 Dec 20.
DOI: 10.1016/j.ejca.2021.11.009
Abstrakt: 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.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.T. reported no relevant conflicts of interest. J.M. declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. A.Z. declares travel support from Novartis, Sanofi Genzyme and Bristol-Myers Squibb, outside the submitted work. R.M. reported no relevant conflicts of interest. E.C. reported no relevant conflicts of interest. G.L. declares travel support from Sun Pharma, outside the submitted work. P.J. reported no relevant conflicts of interest. R.H. declares speakers and advisory board honoraria from BMS, MSD, Novartis, Pierre Fabre, Roche and SUN-Pharma, outside the submitted work. P.T. declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work. J.U. declares advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi, outside the submitted work. C.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. J.Ul declares travel support: Medac, Sun Pharma; consulting: Bristol-Myers Squibb, Sun Pharma; lectures: Bristol-Myers Squibb, MSD, Merck, Novartis, Roche, Sanofi, Sun Pharma; grants: Novartis, outside the submitted work. A.K. reported no relevant conflicts of interest. P.M. declares research support (to institution): Bristol-Myers Squibb, Novartis, MSD. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Bayersdorf, Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN, Merck-Serono, Sanofi, outside the submitted work. R.G. invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, Merck Serono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre, outside the submitted work. F.M. declares travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche, outside the submitted work. E.D. reported no relevant conflicts of interest. M.W. reported no relevant conflicts of interest. J.K. reported no relevant conflicts of interest. I.M. reported no relevant conflicts of interest. A.S. reported no relevant conflicts of interest. A.P. reported no relevant conflicts of interest. E.L. served as a consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. L.Z. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sun Pharma and Novartis, outside the submitted work.E.H. reported no relevant conflicts of interest. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. D.S. reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. K.G.: No relevant conflicts of interest.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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