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

Abstract

Purpose: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization.

Methods: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD 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.

Results: Of the 757 patients who received DPYD 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 (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .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 (P < .001), with reactive carriers having the earliest onset and highest incidence.

Conclusion: DPYD 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.

FIG 1.

CONSORT diagram. A total of 757 patients who underwent DPYD genotyping from March 2020 through May 2023 were evaluated for demographics and implementation metrics (Implementation Cohort). Of these, 442 patients who underwent DPYD genotyping and were initiated on a fluoropyrimidine from March 2020 through December 2022 were followed for 3 months and evaluated for dosing and toxicity outcomes (Outcomes Cohort). Of these, 415 DPYD wild-type patients received standard fluoropyrimidine dosing, and 16 pretreatment testing carriers received genotype-guided dosing. Of the 11 reactive testing carriers, eight received genotype-guided dosing upon result return, two continued standard dose as tolerating therapy, and one had therapy discontinued due to carrier status and grade 3 toxicities. Reasons for nonevaluable patients are described in the diagram.

FIG 2.

Summary of clinical course for DPYD variant carriers with 3-month follow-up data. (A) Eleven reactive carriers had samples collected for testing on or after the date of treatment initiation. (B) All 16 pretreatment carriers had samples collected and results reported by the date of treatment initiation. Timepoints of treatments, dose reductions, dose escalations, grade 3+ toxicities, hospitalizations, treatment discontinuations, and reasons for discontinuation are depicted in the figures.

FIG 3.

Cumulative incidence of fluoropyrimidine-related grade 3+ toxicities and hospitalizations stratified by genotype groups in 442 patients. Cumulative incidence was estimated as 1—Kaplan-Meier survival estimate, and log-rank test was used to compare between genotype groups. All subjects with follow-up time >110 days were censored observations and were truncated at 110 days. (A) Grade 3+ toxicities occurred earlier and at a significantly higher rate in reactive carriers compared with pretreatment carriers and wild-type patients (P < .001). (B) Hospitalizations also occurred earlier and at a significantly higher rate in reactive carriers compared with pretreatment carriers and wild-type patients (P < .001).