Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the *2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and rs67376798 before treatment starts. We implemented the genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of testing for FP dose tailoring in our clinical practice and characterized the gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the test, and this dose tailoring does not affect the treatment efficacy. We also found that the *4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; = 0.019) among FP-treated patients based on the genotype. This makes it a candidate variant for implementation in clinical practice.