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Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time.

ABSTRACT: Objective:Fluoropyrimidine treatment can be optimized based on dihydropyrimidine dehydrogenase (DPD) activity. DPD dysfunction leads to increased exposure to active metabolites, which can result in severe or even fatal toxicity. Methods:We provide an overview of 8 years of DPD diagnostic testing (n?=?1194). Results:Within the study period, our diagnostic test evolved from a single-enzyme measurement using first a radiochemical and then a nonradiochemical assay by ultra HPLC-MS in peripheral blood mononuclear cells with uracil, to a combined enzymatic and genetic test (ie, polymerase chain reaction) followed by Sanger sequence analysis of 4 variants of the DPYD gene (ie, DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G; allele frequencies 0.58%, 0.03%, 0.29%, and 1.35%, respectively). Patients who have 1 of the 4 variants tested (n?=?814) have lower enzyme activity than the overall patient group. The majority of patients with the DPYD*2A variant (83%) consistently showed decreased enzyme activity. Only 24 (25.3%) of 95 patients (tested for 4 variants) with low enzyme activity carried a variant. Complete DPYD sequencing in a subgroup with low enzyme activity and without DPYD*2A variant (n?=?47) revealed 10 genetic variants, of which 4 have not been described previously. We did not observe a strong link between DPYD genotype and enzyme activity. Conclusions:Previous studies have shown that DPD status should be determined before treatment with fluoropyrimidine agents to prevent unnecessary side effects with possible fatal consequences. Our study in combination with literature shows that there is a discrepancy between the DPD enzyme activity and the presence of clinically relevant single nucleotide polymorphisms. At this moment, a combination of a genetic and enzyme test is preferable for diagnostic testing. (Curr Ther Res Clin Exp. 2018; 79:XXX-XXX).

SUBMITTER: Coenen MJH

PROVIDER: S-EPMC6258870 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time.

Coenen Marieke J H MJH Paulussen Aimée D C ADC Breuer Marc M Lindhout Martijn M Tserpelis Demis C J DCJ Steyls Anja A Bierau Jörgen J van den Bosch Bianca J C BJC

Current therapeutic research, clinical and experimental 20181031

<h4>Objective</h4>Fluoropyrimidine treatment can be optimized based on dihydropyrimidine dehydrogenase (DPD) activity. DPD dysfunction leads to increased exposure to active metabolites, which can result in severe or even fatal toxicity.<h4>Methods</h4>We provide an overview of 8 years of DPD diagnostic testing (n = 1194).<h4>Results</h4>Within the study period, our diagnostic test evolved from a single-enzyme measurement using first a radiochemical and then a nonradiochemical assay by ultra HPLC ...[more]

PMID: 30510603

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Project description:BackgroundThe main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations.MethodsThe survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted.ResultsWe received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics.ConclusionsThe EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Dataset Information

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time.

Publications

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time.

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