Patients With Cancer and DPYD Variant Alleles: Outcomes With Reduced-Dose Fluoropyrimidine Therapy

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In an analysis reported in the Journal of Clinical Oncology, Knikman et al found that reduced doses of fluoropyrimidine therapy in patients with cancer with DPYD variant alleles did not result in poorer outcomes vs DPYD wild-type controls receiving full fluoropyrimidine doses.

Study Details

The retrospective matched-pair analysis involved patients from a trial (Alpe-DPD) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% (DPYD*2A and c.1679T>G) reduced fluoropyrimidine dose, and a cohort of DPYD variant carriers treated with similarly reduced doses of fluoropyrimidines during routine clinical care between 2013 and March 2020 at the Netherlands Cancer Institute. Outcomes in the DPYD variant population receiving reduced-dose fluoropyrimidines were compared with matched DPYD wild-type controls receiving full-dose treatment in the combined cohorts.   

Key Points

A total of 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. A total of 93 DPYD variant carriers could be matched to three unique DPYD wild-type controls (n = 279) on the basis of sex, age, primary tumor type, cancer stage, and treatment. The 93 DPYD variant carriers included 61 with c.1236G>A, 25 with DPYD*2A, and 13 with c.2846A>T.

Compared with DPYD wild-type controls receiving full-dose fluoropyrimidines, pooled DPYD variant carriers receiving reduced doses did not have significantly poorer progression-free survival (hazard ratio [HR] = 1.23, 95% confidence interval [CI] =1.00–1.51, P = .053) or overall survival (HR = 0.95, 95% CI = 0.75–1.51, P = .698).   

Compared with DPYD wild-type controls, no significantly poorer progression-free survival was observed among DPYD*2A carriers (HR = 0.95, 95% CI = 0.53–1.70, P = .869) or c.2846A>T carriers (HR = 1.30, 95% CI =  0.57–2.93, P = .535), whereas significantly poorer progression-free survival was observed among c.1236G>A carriers (HR = 1.43, 95% CI = 1.10–1.86, P = .007).

Compared with DPYD wild-type controls, no significantly poorer overall survival was observed among DPYD*2A carriers (HR = 0.61, 95% CI =  0.30–1.26, P = .184), c.2846A>T carriers (HR = 0.97, 95% CI = 0.39–2.44, P = .953), or c.1236G>A carriers (HR = 1.17, 95% CI = 0.82–1.69, P = .385).

The investigators concluded, “In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect progression-free survival and overall survival in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.”

Annemieke Cats, PhD, of the Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Roche Pharmaceuticals and the Dutch Cancer Society. For full disclosures of the study authors, visit

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