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

## TL;DR

This study identifies a new genetic variant linked to severe side effects from a common cancer drug, even after implementing existing genetic testing guidelines.

## Contribution

The study discovers a novel DPYD variant (rs1801158) associated with severe adverse drug events in fluoropyrimidine-treated patients.

## Key findings

- The DPYD*4 allele (rs1801158) is strongly associated with severe ADEs in FP-treated patients.
- Physicians fully accepted DPYD genotype-guided dosing recommendations without affecting treatment efficacy.
- The DPYD*4 allele shows significant odds ratios in both univariate and multivariate analyses.

## Abstract

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD 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 DPYD 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 DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*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; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41–28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.