| Title: |
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. |
| Authors: |
Saint-Ghislain, Mathilde; Derrien, Anne-Céline; Geoffrois, Lionnel; Gastaud, Lauris; Lesimple, Thierry; Negrier, Sylvie; Penel, Nicolas; Kurtz, Jean-Emmanuel; Le Corre, Yannick; Dutriaux, Caroline; Gardrat, Sophie; Barnhill, Raymond; Matet, Alexandre; Cassoux, Nathalie; Houy, Alexandre; Ramtohul, Toulsie; Servois, Vincent; Mariani, Pascale; Piperno-Neumann, Sophie; Stern, Marc-Henri; Rodrigues, Manuel |
| Contributors: |
Université de Lille; CHU Lille; Institut Curie Paris; Unité de génétique et biologie des cancers U830; Institut de Cancérologie de Lorraine - Alexis Vautrin Nancy UNICANCER/ICL; Centre de Lutte contre le Cancer Antoine Lacassagne Nice UNICANCER/CAL; CRLCC Eugène Marquis CRLCC; Centre Léon Bérard Lyon; METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694; Les Hôpitaux Universitaires de Strasbourg HUS; Centre Hospitalier Universitaire d'Angers CHU Angers; Hôpital Saint-André |
| Publication Year: |
2024 |
| Collection: |
LillOA (Lille Open Archive - Université de Lille) |
| Subject Terms: |
MBD4; Hypermutation; Mutational process; Immune checkpoint inhibitor; PD-1; PD-L1; Predictive biomarker |
| Description: |
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. ; 173 |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/octet-stream |
| Language: |
English |
| Relation: |
European Journal of Cancer Care; Eur J Cancer; http://hdl.handle.net/20.500.12210/90029 |
| Availability: |
https://hdl.handle.net/20.500.12210/90029 |
| Accession Number: |
edsbas.F11EEB97 |
| Database: |
BASE |