MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients.
Hypermutation
Immune checkpoint inhibitor
MBD4
Mutational process
PD-1
PD-L1
Predictive biomarker
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
01
03
2022
revised:
24
05
2022
accepted:
17
06
2022
pubmed:
22
7
2022
medline:
1
9
2022
entrez:
21
7
2022
Statut:
ppublish
Résumé
MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease for >12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p < 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e). In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.
Sections du résumé
BACKGROUND
MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI.
METHODS
Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients.
RESULTS
Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease for >12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p < 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e).
CONCLUSIONS
In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.
Identifiants
pubmed: 35863105
pii: S0959-8049(22)00384-7
doi: 10.1016/j.ejca.2022.06.033
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Endodeoxyribonucleases
EC 3.1.-
MBD4 protein, human
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105-112Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.R. received a research grant from and Merck Sharp and Dohme for this work. T. L. received support from Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis. S. N. received research grants from Pfizer and Ipsen; personal fees from Pfizer, Bristol-Myers Squibb, Ipsen, Novartis, Merck Sharp and Dohme and Eisai; non-financial support from Pfizer, Bristol-Myers Squibb, Ipsen, Merck Sharp and Dohme and Eisai. Y. L. received fees from Bristol-Myers Squibb and Merck Sharp and Dohme. All remaining authors have declared no conflicts of interest.