Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.
Br J Cancer
; 130(5): 808-818, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Deficiencia de Dihidropirimidina Deshidrogenasa
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Límite:
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia