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

Helgadottir, Hildur; Ghiorzo, Paola; van Doorn, Remco; Puig, Susana; Levin, Max; Kefford, Richard; Lauss, Martin LU ; Queirolo, Paola; Pastorino, Lorenza and Kapiteijn, Ellen, et al. (2018) In Journal of Medical Genetics
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... (More)

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.

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Journal of Medical Genetics
publisher
BMJ Publishing Group
external identifiers
  • scopus:85054536461
ISSN
0022-2593
DOI
10.1136/jmedgenet-2018-105610
language
English
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yes
id
09060a8e-129d-484f-9e30-c20daac6e4ff
date added to LUP
2018-10-09 15:28:57
date last changed
2019-02-20 11:30:40
@article{09060a8e-129d-484f-9e30-c20daac6e4ff,
  abstract     = {<p>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.</p><p>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.</p><p>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&lt;0.001).</p><p>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.</p>},
  author       = {Helgadottir, Hildur and Ghiorzo, Paola and van Doorn, Remco and Puig, Susana and Levin, Max and Kefford, Richard and Lauss, Martin and Queirolo, Paola and Pastorino, Lorenza and Kapiteijn, Ellen and Potrony, Miriam and Carrera, Cristina and Olsson, Håkan and Höiom, Veronica and Jönsson, Göran},
  issn         = {0022-2593},
  language     = {eng},
  month        = {10},
  publisher    = {BMJ Publishing Group},
  series       = {Journal of Medical Genetics},
  title        = {Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations},
  url          = {http://dx.doi.org/10.1136/jmedgenet-2018-105610},
  year         = {2018},
}