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

PURPOSE DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD 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 DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. METHODS Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G&gt;A and c.2846A&gt;T) or 50% (DPYD*2A and c.1679T&gt;G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. RESULTS In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G&gt;A, 25 DPYD*2A, 13 c.2846A&gt;T, and—when pooled—93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P 5 .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P 5 .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P 5 .007) was found in c.1236G&gt;A variant carriers, whereas no differences were found for DPYD*2A and c.2846A&gt;T carriers. CONCLUSION In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G&gt;A carriers receiving a reduced starting dose.</p

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

PURPOSE: -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. METHODS: Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which variant carriers received a 25% (c.1236G&gt;A and c.2846A&gt;T) or 50% ( *2A and c.1679T&gt;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. RESULTS: In total, 156 variant carriers and 775 wild-type controls were available for analysis. Sixty-one c.1236G&gt;A, 25 *2A, 13 c.2846A&gt;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&gt;A variant carriers, whereas no differences were found for *2A and c.2846A&gt;T carriers. CONCLUSION: 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&gt;A carriers receiving a reduced starting dose