Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

摘要: Summary Background The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD ( DPYD ), including *2A and c.2846A>T. Three other variants— c.1679T>G, c.1236G>A/HapB3, c.1601G>A—have been associated with but no definitive evidence for clinical validity these variants available. primary objective this systematic review meta-analysis was assess c.1601G>A as predictors severe fluoropyrimidine-associated toxicity. Methods We did a literature published before Dec 17, 2014, identify cohort studies investigating associations between (grade ≥3) toxicity patients treated (fluorouracil, capecitabine, or tegafur-uracil single agents, combination anticancer drugs, radiotherapy). Individual patient data were retrieved analysed multivariable analysis obtain an adjusted relative risk (RR). Effect estimates pooled by use random-effects meta-analysis. threshold significance set at p value less than 0·0167 (Bonferroni correction). Findings 7365 eight included c.1679T>G significantly (adjusted RR 4·40, 95% CI 2·08–9·30, A/HapB3 (1·59, 1·29–1·97, A not significant 1·52, 0·86–2·70, p=0·15). Analysis individual types showed consistent c.1236G>A/HapB3 gastrointestinal 5·72, 1·40–23·33, p=0·015; 2·04, 1·49–2·78, c.2846A>T also 2·85, 1·75–4·62, Interpretation are clinically relevant Upfront screening variants, addition established c.2846A>T, recommended improve safety cancer fluoropyrimidines. Funding None.