(139) Impact of Pre-emptive Dihydropyrimidine Dehydrogenase Genetic Testing on Clinical Outcomes in Fluoropyrimidine-Naïve Patients

Poster Abstract:

Background: Dihydropyrimidine dehydrogenase (DPD) is the primary enzyme involved in fluoropyrimidine metabolism. Polymorphisms of the gene encoding DPD (DPYD), occur at a rate of 4-7% and correlate with DPD enzyme deficiency. Failure to detect patients with DPD deficiency and adjust the dosage preemptively may result in severe toxicity, including death. Despite the benefits associated with routine preemptive DPYD testing, clinical practice guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology do not currently support this practice due to the lack of studies examining the timing of DPYD testing in relation to safety outcomes. In contrast, the European Medicines Agency, the French National Agency for the Safety of Medicines and Health Products, and the Medicines and Healthcare Products Regulatory Agency have each approved guidelines for preemptive DPYD testing for patients treated with fluoropyrimidines.

Objective: To evaluate the impact of preemptive versus standard of care DPYD testing on clinical outcomes in fluoropyrimidine-naïve patients

Methods: This study is a single center, retrospective, observational study that includes all patients 18 years and older at DFCI and network locations who received their first lifetime dose of a systemic fluoropyrimidine or had a resulted DPYD test between July 1, 2022, and June 30, 2023. Patients were excluded if they received their first fluoropyrimidine dose outside of DFCI and if they received their first fluoropyrimidine dose as part of a research protocol. Included patients were placed into either the preemptive or standard cohort based on the timing of their DPYD test result in relation to their first fluoropyrimidine dose. The primary endpoints are the composite incidence of hospitalizations and emergency department visits due to fluoropyrimidine toxicity, and the incidence of all-cause mortality within 90 days. Secondary endpoints in patients with DPD deficiency include the incidence of empiric fluoropyrimidine dose reductions, incidence of not receiving a fluoropyrimidine agent, and ability to tolerate fluoropyrimidine dose escalation and whether this correlates with DPYD activity scores and genotypes. Primary endpoints will be analyzed via a time-to-event survival analysis.

Results: A total of 1394 patients were reviewed, and 1325 patients met study inclusion criteria. 585 were placed in the preemptive group, 605 patients were placed in the standard group, and 135 had a DPYD test result but never received a fluoropyrimidine. Of the 881 patients with a resulted DPYD test, 50 patients (5.7%) have confirmed DPD deficiency. The remaining results are pending.

Discussion: pending

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