Carl M Thielmann1, Johanna Matull2, Anne Zaremba2, Rajmohan Murali3, Eleftheria Chorti2, Georg Lodde2, Philipp Jansen2, Rudolf Herbst4, Patrick Terheyden5, Jochen Utikal6, Claudia Pföhler7, Jens Ulrich8, Alexander Kreuter9, Peter Mohr10, Ralf Gutzmer11, Friedegund Meier12, Edgar Dippel13, Michael Weichenthal14, Julia Kretz2, Inga Möller2, Antje Sucker2, Annette Paschen2, Elisabeth Livingstone2, Lisa Zimmer2, Eva Hadaschik2, Selma Ugurel2, Dirk Schadendorf2, Klaus G Griewank15. 1. Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany. Electronic address: carlmaximilian.thielmann@uk-essen.de. 2. Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. 4. Skin Cancer Unit, Helios Klinikum Erfurt, Erfurt, Germany. 5. Department of Dermatology, UKSH Campus Lübeck, Lübeck, Germany. 6. 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. 7. Department of Dermatology, Saarland University Medical School, Homburg, Saar, Germany. 8. Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany. 9. Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Klinik Oberhausen, University Witten/Herdecke, Oberhausen, Germany. 10. Dermatological Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. 11. Skin Cancer Center, Hannover Medical School, Hannover, Germany; Department of Dermatology, Mühlenkreiskliniken Minden, Minden, Germany. 12. Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. 13. Department of Dermatology Ludwigshafen, Klinikum der Stadt Ludwigshafen Am Rhein GGmbH, Ludwigshafen, Germany. 14. Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. 15. Department of Dermatology, University Hospital Essen, University of Duisburg, German Cancer Consortium (DKTK), Partner Site, Essen, Germany. Electronic address: klaus.griewank@uk-essen.de.
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.
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.
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