Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decr...

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Bibliographic Details
Published in:	Journal of oncology pharmacy practice Vol. 29; no. 1; pp. 5 - 13
Main Authors:	Ockeloen, Charlotte W, Raaijmakers, Aron, Hijmans-van der Vegt, Manon, Bierau, Jörgen, de Vos-Geelen, Judith, Willemsen, Annelieke ECAB, van den Bosch, Bianca JC, Coenen, Marieke JH
Format:	Journal Article
Language:	English
Published:	London, England SAGE Publications 01-01-2023 Sage Publications Ltd
Subjects:	Antimetabolites, Antineoplastic - adverse effects Capecitabine - adverse effects Dehydrogenases Dihydrouracil Dehydrogenase (NADP) - genetics Drug dosages Enzymatic activity Enzymes Fluorouracil - adverse effects Genotype Genotypes Genotyping Leukocytes, Mononuclear Original Peripheral blood mononuclear cells Phenotypes Phenotyping Prospective Studies Retrospective Studies Statistical analysis Toxicity fluoropyrimidine toxicity decreased DPD activity DPYD fluoropyrimidines DPD DPD deficiency pharmacogenetics
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Summary:	Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.
ISSN:	1078-1552 1477-092X
DOI:	10.1177/10781552211049144