Fluoropyrimidine-related cardiotoxicity in patients with <i>DPYD</i> variants: A real-world cohort study.

Abstract

e24035 Background: Fluoropyrimidines are foundational agents in gastrointestinal oncology but can cause severe toxicity in patients with reduced dihydropyrimidine dehydrogenase (DPD) activity due to DPYD variants. Although complete DPD deficiency is rare, partial deficiency affects an estimated 3–8% of the U.S. population. Fluoropyrimidine-associated cardiotoxicity includes coronary vasospasm, acute coronary syndrome (ACS), arrhythmia and heart failure. Pretreatment DPYD genotyping enables identification of at-risk patients, yet the relationship between DPYD status and cardiotoxicity remains poorly defined. Methods: We conducted a retrospective study of 158 adults receiving fluoropyrimidine-based chemotherapy at Moffitt Cancer Center between 7/2022-12/2025. Pretreatment DPYD genotyping identified patients with decreased-function variants (n = 31) and a comparator group of DPYD wild-type (WT) patients (n = 127). Medical records were reviewed for cardiotoxicity, defined as new-onset ACS, arrhythmia, or left ventricular dysfunction occurring within 30 days of initiating fluoropyrimidine treatment. Characteristics and outcomes were compared between the DPYD- variant and DPYD -WT groups. Results: Cardiotoxicity occurred in 19.4% of DPYD -variant patients compared to 2.4% of the DPYD -WT patients (Fisher’s exact test, p = 0.002). The WT patients who developed cardiotoxicity had higher average baseline cardiovascular risk scores, and 2 experienced ST-elevation ACS. Among DPYD -variant patients who developed cardiotoxicity, 50% carried the *1/*2A ( c.1905+1G &gt; A ) variant and 33% the *1/ c.2846A &gt; T variant. In the variant group, cardiac events occurred with both infusional 5-FU and capecitabine and included arrhythmia, and non-ST-elevation ACS. Notably, 83% of the DPYD -variant patients who developed cardiotoxicity did not receive upfront genotype-guided fluropyrimidine dose-reduction. Following cardiotoxicity, half of the affected DPYD -variant patients resumed therapy with dose-reduction, while the others permanently discontinued treatment. Conclusions: Cardiotoxicity is a potentially life-threatening complication of fluoropyrimidine chemotherapy. In this study, cardiotoxicity occurred significantly more frequently among patients with DPYD deficiency despite lower baseline cardiovascular risk. These findings suggest that DPYD status may confer increased susceptibility to fluoropyrimidine-associated cardiotoxicity and highlight missed opportunities for genotype-guided dose modification. Integration of pretreatment DPYD genotyping, upfront genotype-guided dose reduction, and enhanced cardiac monitoring into standard care may help mitigate this risk. Further prospective and translational studies are needed to clarify the mechanistic links between DPYD activity and cardiotoxicity and to inform genotype-driven treatment strategies.