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Clinical Studies

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

British Journal of Cancer volume 130, pages 808–818 (2024)Cite this article

Subjects

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.

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Data availability

Individual patient data are not available for sharing. Agreement of the investigators from each study would be necessary to transfer such data. Some summary study-level data are available in this paper. Additional study-level summary data corresponding to the analyses mentioned in the paper may be provided on request.

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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.

Author information

Author notes

  1. These authors contributed equally: Gwénaël Le Teuff, Nathalie Cozic.

  2. These authors jointly supervised this work: Jean-Pierre Pignon, Marie-Christine Etienne-Grimaldi.

  3. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Service de Biostatistique et d’Epidémiologie, Gustave Roussy, Oncostat U1018 INSERM, labeled Ligue Contre le Cancer, Université Paris-Saclay, Villejuif, France

    Gwénaël Le Teuff, Nathalie Cozic & Jean-Pierre Pignon

  2. Service de Biochimie et Biologie Moléculaire, CHU Carémeau, Nîmes, France

    Jean-Christophe Boyer

  3. Department of cancer medicine, Gustave-Roussy Cancer Campus, Paris-Saclay and Paris-Sud Universities, Villejuif, France

    Valérie Boige

  4. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC, 5096, Paris, France

    Valérie Boige, Marie-Anne Loriot & Pierre Laurent-Puig

  5. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, MN, USA

    Robert B. Diasio

  6. Université Paris-Cité, SIRIC CARPEM, Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, AP-HP, Paris, France

    Julien Taieb

  7. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Didier Meulendijks & Jan H. M. Schellens

  8. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

    Claire Palles

  9. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

    Matthias Schwab

  10. Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University of Tuebingen, Tuebingen, Germany

    Matthias Schwab

  11. Cluster of Excellence IFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, 72074, Tübingen, Germany

    Matthias Schwab

  12. Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands

    Maarten Deenen

  13. Department of Clinical Chemistry, Bern University Hospital, University of Bern, Inselspital, Bern, Switzerland

    Carlo R. Largiadèr

  14. Purine Research Laboratory, St Thomas’ Hospital, London, UK

    Anthony Marinaki

  15. Norwich Medical School, University of East Anglia, Norwich, UK

    Barbara A. Jennings

  16. Sahlgrenska University Hospital, Goteborg, Sweden

    Yvonne Wettergren

  17. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Antonello Di Paolo

  18. LMU Munich, University Hospital, Campus Grosshadern, Munich, Germany

    Eva Gross

  19. National Institute of Oncology, Budapest, Hungary

    Barna Budai

  20. College of Heath, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia

    Stephen P. Ackland

  21. Amsterdam UMC, location University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, The Netherlands

    André B. P. van Kuilenburg

  22. Cancer Center Amsterdam, Cancer Biology and Immunology, Imaging and biomarkers, Amsterdam, The Netherlands

    André B. P. van Kuilenburg

  23. Intermountain Precision Genomics, Intermountain Healthcare, St George, UT, USA

    Howard L. McLeod

  24. Oncopharmacology Laboratory, Centre Antoine Lacassagne, Nice, France

    Gérard Milano & Marie-Christine Etienne-Grimaldi

  25. Institut Claudius Regaud, IUCT-Oncopôle and CRCT, University of Toulouse, Inserm, Toulouse, France

    Fabienne Thomas

  26. Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Paris, France

    Marie-Anne Loriot & Pierre Laurent-Puig

  27. Nuffield Division of Clinical and Laboratory Sciences and University of Oxford, Oxford, UK

    David Kerr

  28. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Qian Shi

Authors
  1. Gwénaël Le Teuff
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  2. Nathalie Cozic
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  3. Jean-Christophe Boyer
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  4. Valérie Boige
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  5. Robert B. Diasio
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  6. Julien Taieb
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  7. Didier Meulendijks
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  8. Claire Palles
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  9. Matthias Schwab
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  10. Maarten Deenen
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  11. Carlo R. Largiadèr
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  12. Anthony Marinaki
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  13. Barbara A. Jennings
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  14. Yvonne Wettergren
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  15. Antonello Di Paolo
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  16. Eva Gross
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  18. Stephen P. Ackland
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  19. André B. P. van Kuilenburg
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  20. Howard L. McLeod
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  21. Gérard Milano
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  22. Fabienne Thomas
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  27. Qian Shi
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  28. Jean-Pierre Pignon
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  29. Marie-Christine Etienne-Grimaldi
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Consortia

FUSAFE collaborative group

  • Gwénaël Le Teuff
  • , Nathalie Cozic
  • , Jean-Christophe Boyer
  • , Valérie Boige
  • , Robert B. Diasio
  • , Julien Taieb
  • , Didier Meulendijks
  • , Claire Palles
  • , Matthias Schwab
  • , Maarten Deenen
  • , Carlo R. Largiadèr
  • , Anthony Marinaki
  • , Barbara A. Jennings
  • , Yvonne Wettergren
  • , Antonello Di Paolo
  • , Eva Gross
  • , Barna Budai
  • , Stephen P. Ackland
  • , André B. P. van Kuilenburg
  • , Howard L. McLeod
  • , Gérard Milano
  • , Fabienne Thomas
  • , Marie-Anne Loriot
  • , David Kerr
  • , Jan H. M. Schellens
  • , Pierre Laurent-Puig
  • , Qian Shi
  • , Jean-Pierre Pignon
  •  & Marie-Christine Etienne-Grimaldi

Contributions

GLT, JPP, JCB, MCEG, NC and VB with the help of the steering committee members designed and supervised the study. MCEG, and JPP obtained funding. JPP, MCEG, JCB and the DPD working group (cf. appendix 2) searched and selected the studies. Steering committee members contributed to the identification and selection of the studies. JPP, NC, MCEG and VB collected and checked data with the help of the investigators who validated the re-analysis of their trials. GLT, JPP, and NC did the statistical analyses. GLT, JCB, JPP, MCEG, NC and VB wrote the draft, with revisions from the other investigators. All authors contributed to the interpretation of the results during the investigator meeting and the revision of the manuscript. All investigators listed in Web-Appendix 1 received the manuscript for revision.

Corresponding author

Correspondence to Gwénaël Le Teuff.

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Competing interests

GM reports consulting fees from Servier. JHM Schellens reports patents on oral taxanes. MS reports payment and honoraria for lectures for CED Service GmbH. VB reports consulting fees from Merck, Serono, Bayer, Roche, Eisai and BMS. Q Shi reports grants from Janssen, BMS, Genetech, Novartis, Celgene and fees from Regeneron Pharmaceuticals and Chugai Pharmaceuticals. MC Etienne-Grimaldi reports honoraria for lectures for AMGEN. All other authors report no conflicts of interest.

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Le Teuff, G., Cozic, N., Boyer, JC. et al. Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis. Br J Cancer 130, 808–818 (2024). https://doi.org/10.1038/s41416-023-02517-2

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