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Fluoropyrimidine DPYD Genotype–Guided Dosing in Patients With Cancer

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Key Points

  • A 50% initial dose reduction in DPYD*2A and c.1679T>G carriers appeared to markedly reduce incidence of grade ≥ 3 toxicity.
  • A dose reduction > 25% may be warranted in c.1236G>A and c.2846A>T carriers to further reduce risk of severe toxicity.

In a Dutch study reported in The Lancet Oncology, Henricks et al found that DPYD genotype–guided dosing reduced the frequency of severe fluoropyrimidine toxicity in patients with cancer. Increased fluoropyrimidine toxicity is associated with reduced activity of the metabolic enzyme dihydropyrimidine dehydrogenase (DPD) related to genetic variants in the DPYD gene.

Study Details

In this prospective safety analysis in 17 hospitals in the Netherlands, 1,103 patients with cancer who were planned to begin a fluoropyrimidine-based therapy (capecitabine or fluorouracil as a single agent or in combination with other chemotherapeutic agents or radiotherapy) were screened for the four most relevant DPYD variants, consisting of DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Patients were enrolled between April 2015 and December 2017. 

Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and patients with DPYD wild-type disease received dosing according to the standard of care. The primary endpoint was frequency of severe (grade ≥ 3) adverse events. Relative risks for severe toxicity were compared between the study population and a historical cohort of DPYD variant allele carriers receiving full-dose fluoropyrimidine-based therapy. 

Frequency of Severe Toxicity

In total, 85 patients (8%) were heterozygous DPYD variant allele carriers and 1,018 (92%) were DPYD wild-type patients. Fluoropyrimidine-related severe toxicity occurred in 39% of DPYD variant carriers vs 23% of wild-type patients (= .0013). The relative risk for severe toxicity was 1.31 (95% confidence interval [CI] = 0.63–2.73) for genotype-guided dosing vs 2.87 (95% CI = 2.14–3.86) in the historical cohort for DPYD*2A carriers; no toxicity (1 patient) vs 4.30 (95% CI = 2.10–8.80) in c.1679T>G carriers; 2.00 (95% CI = 1.19–3.34) vs 3.11 (95% CI = 2.25–4.28) for c.2846A>T carriers; and 1.69 (95% CI = 1.18–2.42) vs 1.72 (95% CI = 1.22–2.42) for c.1236G>A carriers.

The investigators concluded, “Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype–based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype–guided individualized dosing should be a new standard of care.”

The study was funded by the Dutch Cancer Society.

Jan H. M. Schellens, MD, of the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, is the corresponding author for The Lancet Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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