Journal article
Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis
British journal of cancer, Vol.130(5), pp.808-818
01/15/2024
DOI: 10.1038/s41416-023-02517-2
PMCID: PMC10912560
PMID: 38225422
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.
Details
- Title: Subtitle
- Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis
- Creators
- Gwénaël Le Teuff - Institut Gustave RoussyNathalie Cozic - Institut Gustave RoussyJean-Christophe Boyer - Centre Hospitalier Universitaire de NîmesValérie Boige - Institut Gustave RoussyRobert DiasioJulien Taieb - Direction des Applications MilitairesDidier MeulendijksClaire PallesMatthias Schwab - University of TübingenMaarten DeenenCarlo LargiadèrAnthony MarinakiBarbara JenningsYvonne WettergrenAntonello Di PaoloEva Gross - Ludwig-Maximilians-Universität MünchenBarna Budai - National Institute of OncologyStephen AcklandAndré van Kuilenburg - Amsterdam UMC Location University of AmsterdamHoward McleodGérard MilanoFabienne Thomas - Université Fédérale de Toulouse Midi-PyrénéesMarie-Anne LoriotDavid KerrJan SchellensPierre Laurent-PuigQian ShiJean-Pierre PignonMarie-Christine Etienne-Grimaldi
- Resource Type
- Journal article
- Publication Details
- British journal of cancer, Vol.130(5), pp.808-818
- DOI
- 10.1038/s41416-023-02517-2
- PMID
- 38225422
- PMCID
- PMC10912560
- NLM abbreviation
- Br J Cancer
- ISSN
- 0007-0920
- eISSN
- 1532-1827
- Publisher
- Cancer Research UK
- Grant note
- French Ministry of Health: PHRC-K 14-193 FUSAFE French << Ligue Nationale Contre le Cancer >>
The authors would like to thank the Gustave Roussy library team (current head: Alexia Nerfie) 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.
- Language
- English
- Date published
- 01/15/2024
- Academic Unit
- Biostatistics
- Record Identifier
- 9984810999202771
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