Transitioning from reactive to pretreatment DPYD testing through a system-wide screening program at a comprehensive cancer center.

Abstract

544 Background: Fluoropyrimidines (FP), including 5-fluorouracil and capecitabine, are among the most commonly used systemic anticancer therapies. Deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene, is associated with an increased risk of severe, potentially life-threatening FP-related toxicity. Historically, DPYD testing at our institution was performed reactively in patients with greater than expected toxicity rather than routinely before FP initiation. We evaluated the impact of a system-wide initiative designed to support pretreatment DPYD screening. Methods: A multidisciplinary team at a large comprehensive cancer center developed and implemented a pretreatment DPYD testing program designed to identify patients at risk for FP toxicity before treatment initiation. Beginning in October 2025, following the FDA initiation of a black box warning for capecitabine, interventions included provider education, updated patient education materials, electronic health record-based clinical decision support, and pharmacist-initiated safeguards to reduce missed or unaddressed results. The primary outcome was the change in monthly DPYD testing volume following implementation. Secondary outcomes included frequencies of abnormal DPYD results and variants of uncertain significance (VUS). Comparisons were performed using chi-square testing, with odds ratios (OR) and 95% confidence intervals (CI) reported where appropriate. Results: Between January 2021 and June 1, 2026, 2,086 DPYD tests were completed, including 588 before and 1,498 after implementation. Average testing volume increased from 10 tests/month before implementation to 166 tests/month after implementation, representing a 16-fold increase. Among patients tested, the proportion of abnormal results decreased from 9.5% before implementation to 4.5% after implementation (OR 0.45, 95% CI 0.31-0.65; p<0.0001). The VUS frequency was unchanged following implementation (2.7% vs 1.9%; OR 0.68, 95% CI 0.37-1.27; p=0.22). Conclusions: Implementation of a system-wide pretreatment DPYD testing program resulted in a 16-fold increase in DPYD testing at a large comprehensive cancer center. The decreased frequency of abnormal DPYD results following implementation reflects expansion from reactive testing to routine pretreatment screening. These findings demonstrate the feasibility of multidisciplinary, systems-based approaches to implement pharmacogenomic testing at scale and improve identification of patients at risk for severe FP toxicity.