Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (<i>DPYD</i>) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

Abstract

Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain <i>DPYD</i> genetic variants with standard dosing. We implemented <i>DPYD</i> genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five <i>DPYD</i> variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. Of the 757 patients who received <i>DPYD</i> genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (<i>P</i> = .085); 64%, 25%, and 13% were hospitalized (<i>P</i> < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (<i>P</i> = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (<i>P</i> < .001), with reactive carriers having the earliest onset and highest incidence. <i>DPYD</i> genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.