Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis
2 U1018 (Équipe 2) - CESP - Oncostat
3 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
4 IGR - Institut Gustave Roussy
5 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
6 CNRS - Centre National de la Recherche Scientifique
7 Mayo Clinic [Rochester]
8 SIRIC CARPEM - Cancer Research and Personalized Medicine - CARPEM [Paris]
9 Service de gastroenterologie [CHU HEGP]
10 NKI - Netherlands Cancer Institute
11 University of Birmingham [Birmingham]
12 Eberhard Karls Universität Tübingen = University of Tübingen
13 Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology [Stuttgart]
14 Catharina Hospital = Catharina Ziekenhuis
15 Inselspital - Bern University Hospital [Berne]
16 Guy's and St Thomas' Hospital [London]
17 UEA - University of East Anglia [Norwich]
18 Sahlgrenska University Hospital [Gothenburg]
19 UniPi - University of Pisa [Italy] = Università di Pisa [Italia] = Université de Pise [Italie]
20 University Hospital LMU Munich
21 National Institute of Oncology [Budapest, Hungary]
22 UoN - University of Newcastle [Callaghan, Australia]
23 Amsterdam UMC - Amsterdam University Medical Centers
24 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
25 CRCT - Centre de Recherches en Cancérologie de Toulouse
26 Oncopole Claudius Regaud
27 HEGP - Hôpital Européen Georges Pompidou [APHP]
28 Nuffield - Nuffield
29 INSERM - Institut National de la Santé et de la Recherche Médicale
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Résumé
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 6.7u201313.5]) 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 1.2u20132.7]), 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.