The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC^®) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline‐for‐fluoropyrimidines‐and‐dpyd/).

We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study. Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade 3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5′-UTR VNTR and TYMS 3′-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P16 ng ml⁻¹) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity. High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4–5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.