Clinical implementation and outcome evaluation of dihydropyrimidine dehydrogenase (DPYD) pharmacogenomic testing for fluoropyrimidine dosing in a Canadian Provincial Healthcare center.

Background: 5-Fluorouracil (5-FU) and its pro-drug, capecitabine, are widely used to treat solid tumors. Patients with dihydropyrimidine dehydrogenase (DPYD) deficiency are at increased risk for severe treatment-related toxicity. This study reported the implementation of DPYD genotyping in clinical practice and assessed the impact of genotype-guided dosing on clinical outcomes.

Methods: An in-house pharmacogenomic testing using the Elucigene DPYD genotyping kit (Yourgene Health, UK) was established to detect the four most common clinically actionable DPYD alleles, including *2A, *13, HapB3 and c.2846A>T (rs67376798). Six months post-implementation, a retrospective chart review assessed genotype results, chemotherapy regimens, dose modifications, adverse events related to 5-FU or capecitabine, and demographics. Data were de-identified for analysis.

Results: Analytical validation of the DPYD assay showed 100 % sensitivity, specificity, accuracy, reproducibility, and repeatability. The genotyping workflow was successfully integrated into clinical practice, with a rapid turnaround time to meet oncology treatment planning. From July to December 2024, 299 patients underwent DPYD testing; variants were identified in 22 patients, including 20 patients (6.7 %) with clinically significant variants conferring a reduced DPD function and 2 patients with a variant (c.483 + 18G>A; rs56276561) that retains normal DPD function. Among those variants, HapB3 (n = 18) was the most frequent one, characterized by c.1129-5923C>G and c.1236G>A (rs75017182, rs56038477) co-occurring with c.483 + 18G>A (rs56276561). Of 233 patients receiving 5-FU-based chemotherapy, 13 were variant carriers. Genotype-guided dosing allowed early dose optimization, and all carriers completed at least three treatment cycles, with one severe adverse event attributed to oxaliplatin rather than 5-FU.

Conclusions: This study reported the integration of DPYD pharmacogenomic testing into oncology care and evaluated the post-implementation clinical outcomes, highlighting the critical role of pharmacogenomic testing in optimizing cancer treatment and improving patient safety.