Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis

-guided fluoropyrimidine dosing improves patient safety in carriers of 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 variant carriers treated with a reduced dose and 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 variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% ( *2A and c.1679T>G) reduced dose and data from variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each variant carrier was matched to three wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. In total, 156 variant carriers and 775 wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 *2A, 13 c.2846A>T, and-when pooled-93 variant carriers could each be matched to three unique wild-type controls. For pooled variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; = .698) were not negatively affected by -guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; = .007) was found in c.1236G>A variant carriers, whereas no differences were found for *2A and c.2846A>T carriers. In this exploratory analysis, -guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.