National trends in dihydropyrimidine deficiency testing before fluoropyrimidine chemotherapy.
Abstract
536 Background: In 2025, the Food and Drug Administration and National Comprehensive Cancer Centers Network updated their guidelines to recommend screening for genetic dihydropyrimidine dehydrogenase deficiency (DPYD) prior to administration of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine). Patients with certain DPYD mutations (~3-8% of the population) can poorly metabolize fluoropyrimidine chemotherapy, and for some the enzymatic deficiency is severe enough to result in rapidly fatal toxicity. National trends of this pre-chemotherapy pharmacogenomic testing have not been described. Methods: Retrospective cohort study using national Epic Cosmos electronic health records, limited to the subset of Cosmos practices contributing encounter-level, longitudinal records. We identified first-time administrations of fluoropyrimidine chemotherapy per patient from 2016 through the first quarter of 2026, and linked DPYD genotyping test instances. We also identified use of fluoropyrimidine antidote (uridine triacetate). After descriptive characteristics, we estimated toxicity-related hospital visits within 10 days of chemotherapy between DPYD tested and non-tested patients, then estimated annual trends of pre-chemotherapy DPYD testing. Results: We identified 97,248 patients with first-time fluoropyrimidine chemotherapy (44.6% female; 44.9% age 65+; 67.2% White, 11.9% Black, 2.7% Asian; 5.8% Hispanic; 35.9% commercially insured, 4.6% Medicaid; 94.2% for colorectal/gastrointestinal cancer) and 11,438 instances of DPYD testing. Of the completed DPYD tests, only 1,744 occurred on the same day or before a first-time chemotherapy (1.8% of administrations), but 726 occurred after first-time chemotherapy, and 8,968 (78.4%) of the tests were not associated with a chemotherapy administration. We noted 34 uses of uridine triacetate. Trends of pre-chemotherapy DPYD testing prior to 2023 were consistently under 2.1% but rose to 6.5% in 2025 and 16.5% through the first quarter of 2026. Patients with pre-chemotherapy DPYD testing had significantly lower rates of toxicity-related hospitalizations within 10 days compared to those who did not have DPYD testing prior (9.4% vs. 13.2%; p < 0.001), with an estimated risk difference of -3.8 percentage points (95% CI: -5.19 to -2.42). Conclusions: Despite recognition of DPYD-based toxicity to fluoropyrimidine chemotherapy since the 1980s, pre-chemotherapy testing for DPYD was low through 2024. However, rates of testing rose nearly 8-fold by the first quarter of 2026 compared to 2024. Trends in of pre-chemotherapy dihydropyrimidine dehydrogenase deficiency testing. Year First-time chemotherapy, n Pre-chemotherapy DPYD test, n Pre-chemotherapy DPYD test rate, % 2026 (Q1 only) 3,303 544 16.5 2025 10,046 651 6.5 2024 10,366 220 2.1 2023 10,038 104 1.0 2022 9,914 134 1.4 2021 8,887 48 0.5 2020 8,373 12 0.1 2019 8,520 9 0.1 2018 7,595 7 0.1