Journal
EUROPEAN JOURNAL OF CANCER
Volume 173, Issue -, Pages 105-112Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2022.06.033
Keywords
MBD4; Hypermutation; Mutational process; Immune checkpoint inhibitor; PD-1; PD-L1; Predictive biomarker
Categories
Funding
- BristolMyers Squibb
- European Commission [666003]
- Institut National de la Santeet de la Recherche Medicale (INSERM)
- Institut Curie
- Ligue Nationale Contre le Cancer (Labellisation),
- Programme de Recherche Translationnelle en Cancerologie [PRT-K1951]
- Site de Recherche Integree sur le Cancer (SiRIC) de l' Institut Curie
- EQUIPEX investissements d'avenir program [ANR-10-EQPX03]
- Agence Nationale de le Recherche [ANR10-INBS-09e08]
- Merck Sharp and Dohme
- INCa-DGOS
Ask authors/readers for more resources
In patients with metastatic uveal melanomas, MBD4 mutations are associated with response to immune checkpoint inhibitors, progression-free survival, and overall survival benefits. MBD4 could serve as a predictive biomarker for the efficacy of ICI treatment.
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. (C) 2022 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available