Tools
ToolsLe Teuff, Gwénaël, Cozic, Nathalie, Boyer, Jean-Christophe, Boige, Valérie, Diasio, Robert B., Taieb, Julien, Meulendijks, Didier, Palles, Claire, Schwab, Mattias, Deenen, Maarten J., Largiadèr, Carlo R., Marinaki, Anthony, Jennings, Barbara A., Wettergren, Yvonne, Di Paolo, Antonello, Gross, Eva, Budai, Barna, Ackland, Stephen P., van Kuilenburg, André B. P., McLeod, Howard L., Milano, Gérard, Thomas, Fabienne, Loriot, Marie-Anne, Kerr, David J., Schellens, Jan H. M., Laurent-Puig, Pierre, Shi, Qian, Pignon, Jean-Pierre and Etienne-Grimaldi, Marie-Christine and FUSAFE collaborative group (2024) Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis. British Journal of Cancer, 130 (5). 808–818. ISSN 0007-0920
Preview |
PDF (Manuscript_FINAL_for_publication_Ref_JCB)
- Accepted Version
Download (438kB) | Preview |
Abstract
Background: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Methods: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Results: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7–13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2–2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. Conclusions: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
| Item Type: | Article |
|---|---|
| Additional Information: | Acknowledgements: The authors would like to thank the Gustave Roussy library team (current head: Alexia Nerfié) for its support in the literature search. This study was supported by the French Ministry of Health (PHRC-K 14-193 FUSAFE) and the French « Ligue Nationale Contre le Cancer ». The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Population Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 09 Dec 2023 01:39 |
| Last Modified: | 19 Feb 2025 09:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/93927 |
| DOI: | 10.1038/s41416-023-02517-2 |
Downloads
Downloads per month over past year
Actions (login required)
 |
View Item |