Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations

• Published in: Journal of medical genetics Vol. 57; no. 5; pp. 316 - 321
• Main Authors: Helgadottir, Hildur, Ghiorzo, Paola, van Doorn, Remco, Puig, Susana, Levin, Max, Kefford, Richard, Lauss, Martin, Queirolo, Paola, Pastorino, Lorenza, Kapiteijn, Ellen, Potrony, Miriam, Carrera, Cristina, Olsson, Håkan, Höiom, Veronica, Jönsson, Göran
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2020; BMJ Publishing Group
• Series: Short report
• Subjects: Age; Cancer and Oncology; Cancer Genetics; Cancer och onkologi; Cancer therapies; cdkn2a; Cell cycle; Chemotherapy; Clinical Medicine; Clinical trials; CTLA-4 protein; deletions; Dermatologi och venereologi; Dermatologi och venerologi; Dermatology and Venereal Diseases; familial melanoma; Genes; Genetics & Heredity; high-risk; Immune response; Immunotherapy; ipilimumab; Klinisk medicin; Lymphocytes; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Melanoma; Metastases; Metastasis; metastatic melanoma; Mutation; mutation burden; Neoantigens; nivolumab; Patients; PD-1 protein; Risk factors; Studies; tumor; Tumors; cdkn2a; familial melanoma; tumor mutation burden; metastatic melanoma; immunotherapy
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2018-105610

BackgroundInherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated.Methods CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers’ responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load.ResultsEleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001).ConclusionPatients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.