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

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发表日期：

2024年1月15日

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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

摘要

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.