Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis

Le 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. ORCID: https://orcid.org/0000-0003-3792-9182, 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. 808–818. ISSN 0007-0920

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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
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Depositing User: LivePure Connector
Date Deposited: 09 Dec 2023 01:39
Last Modified: 07 Mar 2024 10:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/93927
DOI: 10.1038/s41416-023-02517-2

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