Implementation and early outcomes of an in-house DPYD genotyping program for fluoropyrimidine safety.

DPYD

Reduced dihydropyrimidine dehydrogenase activity caused by DPYD variants exposes patients to severe fluoropyrimidine toxicity, hence genotype-guided dose reduction from the first cycle.

Pretreatment DPYD genotyping is guideline-supported, yet implementation remains inconsistent when testing, interpretation and result reporting are not integrated into routine care pathways. This prospective observational cohort, conducted from May 2024 to July 2025 at a multisite community-academic cancer centre, evaluates an in-house genotyping programme using TaqMan (c.1905+1G>A, c.1679T>G, c.1236G>A as a proxy for c.1129-5923C>G, c.2846A>T and c.557A>G) embedded in the prechemotherapy workflow, with an automated pipeline that generates a note released into the electronic health record after medical director review. Of 617 genotyped patients, 505 who received fluoropyrimidine-based therapy were analysed: 439 (86.9%) were tested before treatment, but only 197 of 439 (44.9%) had a result available before cycle 1. Twenty-two patients (4.4%) were heterozygous for a DPYD variant (c.1236G>A in 11, c.2846A>T in 5, c.1905+1G>A in 4, c.557A>G in 2); in the pretreatment cohort, 10 of 21 heterozygous patients (47.6%) had a dose reduction at cycle 1, 9 of them documented as genotype-guided. Severe adverse events requiring urgent evaluation or hospitalisation occurred in 5 of 505 patients (1.0%), one of them heterozygous for c.1236G>A with a result returned after treatment had started.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The useful result is organisational: the limiting factor is not assay turnaround but returning the result before the first treatment decision, since only 44.9% of patients tested before treatment had it by cycle 1, so changing genotyping technology would not solve the problem. The clinical data are too thin to conclude: 5 severe events in all, only one tied to a carrier with a late result, and no comparator to quantify what the 9 genotype-guided dose reductions prevented. This is a feasibility demonstration, which argues for locking the reporting time into the prescribing pathway before reading it as proof of benefit.

Analysis by Dr Thibaut Benquey