Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.
Le Teuff G., Cozic N., Boyer J-C., Boige V., Diasio RB., Taieb J., Meulendijks D., Palles C., Schwab M., Deenen M., Largiadèr CR., Marinaki A., Jennings BA., Wettergren Y., Di Paolo A., Gross E., Budai B., Ackland SP., van Kuilenburg ABP., McLeod HL., Milano G., Thomas F., Loriot M-A., Kerr D., Schellens JHM., Laurent-Puig P., Shi Q., Pignon J-P., Etienne-Grimaldi M-C., FUSAFE collaborative group None.
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