Implementation of <i>DPYD</i> genotyping in response to FDA black box warning: Initial experience at a comprehensive cancer center.

Abstract

e15139 Background: A subset of DPYD polymorphisms contribute to poor catabolism of fluoropyrimidines, resulting in increased risk of drug toxicity and even death. In 2025, the FDA recommended dihydropyrimidine dehydrogenase ( DPYD ) pharmacogenomic testing prior to fluoropyrimidine (FP) initiation. We describe implementation of mandatory DPYD testing into institutional workflow. Methods: DPYD pharmacogenomic testing was implemented 11/4/2025 at Memorial Sloan Kettering Cancer Center (MSK) prior to therapy with any FP using an in-house, CLIA and New York State approved blood-based assay. Testing of all 7 DPYD Tier 1 germline variants recommended by international professional societies was performed using a quantitative PCR-based approach (APIS Assay Technologies Ltd.) with results returned within 5 days from blood draw. We developed patient education materials, integrated New York State-required e-consent, notification to order testing, Genomic Indicator assignment, and hard stops preventing FP treatment verification and/or pharmacy release without DPYD results. A strategy for documenting exemptions and multidisciplinary communication was integrated into the Epic workflow. We describe implementation, detection rate, and treatment impact. Results: Among 604 tested patients, 27 (4.5%) harbored a DPYD polymorphism inclusive of patients with GI (n = 22), head and neck (n = 3), or breast (n = 2) cancers, with 20 receiving palliative intent treatment. Variants represented included c.1129-5923C &gt; G (n = 19); c.1905+1G &gt; A (n = 3), c.557A &gt; G (n = 3), and c.868A &gt; G (n = 2). 18 have had treatment modifications, 7 have had no treatment plan alteration and 2 are pending decisions. Among the 18 patients with altered treatment plans, 2 were prescribed non-FP regimens and 16 were administered FP dose-reductions ranging from 25-83% in dose-intensity for the first dose. Of the 16 who had dose-reduction, escalation after the first cycle was possible in 8 patients (4/8 to full dose). All patients tolerated therapy at initial and re-escalation doses without significant toxicity. Toxicities reported were dry mouth/lips (n = 2), diarrhea (n = 2), fatigue (n = 1), all grade 1 by CTCAE v5. Of the 7 patients where no treatment modification was initiated, 5 underwent testing in anticipation of future need for FP while 2 patients needed emergent treatment, both with intermediate DPYD activity who received full-dose therapy without exhibiting associated toxicity. Updated yield of universal DPYD testing and follow-up based on our experience through 4/2026 will be presented. Conclusions: MSK introduced mandatory e-consent and in-house DPYD testing prior to FP therapy in 11/2025. Polymorphisms were identified in 4.5% of the tested population and frequently led to treatment modifications. This implementation experience provides a framework for practices seeking to scale pharmacogenomic testing.