Survival of Patients With Cancer With <i>DPYD</i> Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis.

Abstract

<i>DPYD</i>-guided fluoropyrimidine dosing improves patient safety in carriers of <i>DPYD</i> variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between <i>DPYD</i> variant carriers treated with a reduced dose and <i>DPYD</i> wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which <i>DPYD</i> variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% (<i>DPYD</i>*2A and c.1679T>G) reduced dose and data from <i>DPYD</i> variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each <i>DPYD</i> variant carrier was matched to three <i>DPYD</i> wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. In total, 156 <i>DPYD</i> variant carriers and 775 <i>DPYD</i> wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 <i>DPYD</i>*2A, 13 c.2846A>T, and-when pooled-93 <i>DPYD</i> variant carriers could each be matched to three unique <i>DPYD</i> wild-type controls. For pooled <i>DPYD</i> variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; <i>P</i> = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; <i>P</i> = .698) were not negatively affected by <i>DPYD</i>-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; <i>P</i> = .007) was found in c.1236G>A variant carriers, whereas no differences were found for <i>DPYD</i>*2A and c.2846A>T carriers. In this exploratory analysis, <i>DPYD</i>-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled <i>DPYD</i> variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.