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

Hildur Helgadottir, Paola Ghiorzo, Remco van Doorn, Susana Puig, Max Levin, Richard Kefford, Martin Lauss, Paola Queirolo, Lorenza Pastorino, Ellen Kapiteijn, Miriam Potrony, Cristina Carrera, Håkan Olsson, Veronica Höiom, Göran Jönsson

Research output: Contribution to journalArticlepeer-review

16 Citations (SciVal)

Abstract

BACKGROUND: Inherited 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.

RESULTS: Eleven 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).

CONCLUSION: Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.

Original languageEnglish
Pages (from-to)316-321
JournalJournal of Medical Genetics
Volume57
Issue number5
Early online date2018 Oct 5
DOIs
Publication statusPublished - 2020

Subject classification (UKÄ)

  • Cancer and Oncology
  • Dermatology and Venereal Diseases

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