Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?
advanced melanoma
immune checkpoint inhibitors
pathogenic/likely pathogenic germline variant
resistance to immunotherapy
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
28 Apr 2020
28 Apr 2020
Historique:
received:
24
03
2020
revised:
24
04
2020
accepted:
27
04
2020
entrez:
2
5
2020
pubmed:
2
5
2020
medline:
2
5
2020
Statut:
epublish
Résumé
Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11-15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01-4.64; The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.
Sections du résumé
BACKGROUND
BACKGROUND
Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients.
METHODS
METHODS
We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis.
RESULTS
RESULTS
Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11-15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01-4.64;
CONCLUSIONS
CONCLUSIONS
The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.
Identifiants
pubmed: 32354124
pii: cancers12051101
doi: 10.3390/cancers12051101
pmc: PMC7281129
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : TÜFF Habilitation Program for Women of the Faculty of Medicine Tuebingen
ID : 2521-0-0
Organisme : Bundesministerium für Bildung und Forschung
ID : KMU-innovative initiative
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