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. 2025 Nov 1;157(9):1898-1911.
doi: 10.1002/ijc.70005. Epub 2025 Jun 19.

Real-world study on fluoropyrimidine-related toxicity outcomes in cancer patients with select DPYD variant alleles that received DPYD genotype-guided dosing

Sofía L J Peeters  1   2 , Didier Meulendijks  3 , Zerina Kadric  1 , Sara Ibrovic  1 , Geert-Jan Creemers  4 , Vanja Milosevic  5 , Matthijs van de Poll  6 , Lieke H J Simkens  7 , Birgit A L M Deiman  8 , Hans Gelderblom  9 , Henk-Jan Guchelaar  2 , Anna M J Thijs  4 , Maarten J Deenen  1   2
Affiliations

Real-world study on fluoropyrimidine-related toxicity outcomes in cancer patients with select DPYD variant alleles that received DPYD genotype-guided dosing

Sofía L J Peeters et al. Int J Cancer. .

Abstract

DPYD gene variations are associated with severe fluoropyrimidine toxicity, and an initial 50% dose reduction is widely recommended for heterozygous carriers of relevant DPYD variants, including DPYD*2A, DPYD*13, c.2846A>T, and c.1236G>A. However, there is a high variability in DPD activity between DPYD variant carriers, and a proportion of patients may tolerate higher fluoropyrimidine doses. The aim of this retrospective study was to compare fluoropyrimidine toxicity outcomes and tolerated dose intensities between different DPYD variant carriers that received DPYD genotype-guided dosing. We identified DPYD variant carriers that received fluoropyrimidine-based treatment between January 2015 and February 2021 in three Dutch Hospitals. The initial fluoropyrimidine dose was reduced by 25-50% for all heterozygous DPYD variant carriers following the Dutch Pharmacogenetics Working Group guideline. Toxicity outcomes were collected for the first three cycles. From 2112 consecutively DPYD-genotyped patients, 120 patients with DPYD variants were included. The frequency of overall severe toxicity was 21% for wild types, 27% for heterozygous DPYD variant carriers overall, 19% for c.1236G>A carriers, 38% for c.2846A>T carriers, and 44% for DPYD*2A carriers. Median relative dose intensity for cycles 1-3 was 71% for c.1236G>A carriers, 68% for c.2846A>T carriers, and 52% for DPYD*2A carriers. Despite good fluoropyrimidine tolerance in a large proportion of patients, only 13% of patients underwent dose escalation. Novel studies are highly needed to establish the optimal fluoropyrimidine starting dose for heterozygous carriers of c.1236G>A. After initial dose reduction, dose uptitration based on individual tolerance and therapeutic drug monitoring in all DPYD variant heterozygotes is advised to prevent the risk of underdosing.

Keywords: 5‐fluorouracil; DPYD; capecitabine; dihydropyrimidine dehydrogenase; precision dosing.

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Conflict of interest statement

D. Meulendijks was an employee of AstraZeneca Farmaceutica, SA, Spain at the time of finalizing this work and a shareholder of AstraZeneca plc, UK. This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. The other authors have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
Flow diagram of study population selection.
FIGURE 2
FIGURE 2
Overview of relative dose intensity during the first three fluoropyrimidine‐based treatment cycles in heterozygous carriers of variants DPYD*2A, DPYD*13, c.1236G>A, and c.2846A>T included in the primary analysis. N, number of patients. Heterozygous c.1236G>A and c.2846A>T variant carriers were divided into two groups: low starting dose (relative dose intensity <65% in cycle 1; blue) and high starting dose (relative dose intensity ≥65% in cycle 1; black). (A) Heterozygous carriers of DPYD*2A variant; (B) heterozygous carriers of DPYD*13 variant; (C) heterozygous carriers of c.1236G>A variant; (D) heterozygous carriers of c.2846A>T variant.
FIGURE 3
FIGURE 3
Fluoropyrimidine relative dose intensity trends during treatment cycles 1–3 for individual heterozygous DPYD variant carriers included in the primary analysis. Each line represents one patient. FP, fluoropyrimidine. (A) Heterozygous carriers of DPYD*2A variant; (B) heterozygous carriers of DPYD*13 variant; (C) heterozygous carriers of c.1236G>A variant; (D) heterozygous carriers of c.2846A>T variant.
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