DPYD Variants to Predict 5-FU Toxicity: The Ultimate Proof

Based upon the evidence that pyrimidinemia was familial and caused by a genetic deficiency in the dihydropyrimidine dehydrogenase gene ( DPYD ) ( 1 ), the seminal discovery on the heritability of 5-fluorouracil (5-FU) toxicity ( 2 ) opened the gate to the flood of studies on the genetic predisposition to severe toxicity in patients treated with fluoropyrimidines. In this issue of the Journal, Lee et al. ( 3 ) report the results of a pharmacogenetic study in colorectal cancer patients treated with 5-FU–based therapy in the adjuvant setting. It provides the ultimate evidence for variation in the DPYD locus as a major determinant of patient safety. *2A and D949V are two DPYD variants with a strong effect size (odds ratios [ORs] of 15.21 and 9.10, respectively) for “5-FU-related” grade 3 or higher toxicities, with a strong association also for all grade 3 or higher toxicities. Hence, the occurrence of these heritable variants poses a considerable risk for patients and a challenge to patient management to preserve dose intensity.