- Title
- Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis
- Creator
- Le Teuff, Gwénaël; Cozic, Nathalie; 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.; Boyer, Jean-Christophe; Milano, Gérard; Thomas, F; Loriot, M-A; Kerr, D; Schellens, JHM; Laurent-Puig, P; Shi, Q; Pignon, J-P; Etienne-Grimaldi, M-C; Boige, Valérie; Diasio, Robert b.; Taieb, Julien; Meulendijks, Didier; Palles, Claire; Schwab, Matthias; Deenen, Maarten
- Relation
- British Journal of Cancer Vol. 130, p. 808-818
- Publisher Link
- http://dx.doi.org/10.1038/s41416-023-02517-2
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2024
- Description
- 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.
- Subject
- dihydropyrimidine dehydrogenase (DPD); toxicities; data analysis; patients; SDG 3; Sustainable Development Goal
- Identifier
- http://hdl.handle.net/1959.13/1510272
- Identifier
- uon:56366
- Identifier
- ISSN:0007-0920
- Language
- eng
- Reviewed
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