Toxic responses to fluoropyrimidines frequently stem from variations in DPYD, the gene coding for dihydropyrimidine dehydrogenase (DPD). Identifying DPYD variants allows clinicians to individualize treatment to lower the risk of fluoropyrimidine-associated adverse effects while still achieving effective drug exposure. A multiplex qPCR test was created in-house to detect six DPYD polymorphisms. This assay was offered prospectively to every patient beginning fluoropyrimidine therapy at the BC Cancer Centre in Vancouver and subsequently throughout British Columbia, Canada, and was also used retrospectively for individuals suspected of having toxicity. Dose modifications were implemented for carriers of deleterious variants. Rates of toxicity during the initial three treatment cycles were assessed in carriers versus non-carriers. After an introductory rollout period, the test became accessible across the province.
Over a 9-month interval, 186 individuals underwent testing, with 14 identified as heterozygous for a variant. Toxicity linked to fluoropyrimidines occurred more frequently among carriers. Among 127 non-carriers who completed therapy, 18 (14%) developed grade ≥3 adverse events (CTCAE v5.0). Notably, 22% of the heterozygous patients (3 individuals) exhibited severe toxicity despite dose reductions based on DPYD. In one case, presenting with marked thrombocytopenia within the first week, early genotyping likely prevented a fatal reaction. When variant carriers tolerated initial reduced dosing, a subsequent 25% dose escalation triggered treatment cessation. Consequently, guidance was issued recommending that clinicians increase doses by only 10% after two toxicity-free cycles in this population. Dose adjustments derived from DPYD genotyping were practical and effective for limiting major toxicity in carriers. Nonetheless, some carriers experienced significant fluoropyrimidine toxicity even after reduction, reinforcing the need to strictly follow dosing guidelines. After the pilot period, DPYD testing was implemented province-wide in British Columbia.
