Dataset Information

DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

ABSTRACT:

Background

In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity.

Objectives

The objective of this study is to present the current evidence for DPD testing in routine oncological practice.

Methods

Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk.

Findings

Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively.

Conclusions

The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity.

SUBMITTER: Paulsen NH

PROVIDER: S-EPMC9826411 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

Paulsen Niels Herluf NH Vojdeman Fie F Andersen Stig Ejdrup SE Bergmann Troels K TK Ewertz Marianne M Plomgaard Peter P Hansen Morten Rix MR Esbech Peter Skov PS Pfeiffer Per P Qvortrup Camilla C Damkier Per P

Basic & clinical pharmacology & toxicology 20220908 5

<h4>Background</h4>In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to ...[more]

PMID: 35997509

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Project description:BackgroundThe chemotherapeutic agent 5-fluorouracil (5-FU) is catabolized by dihydropyrimidine dehydrogenase (DPD), the deficiency of which may lead to severe toxicity or death. Since 2019, DPD deficiency testing, based on uracilemia, is mandatory in France and recommended in Europe before initiating fluoropyrimidine-based regimens. However, it has been recently shown that renal impairment may impact uracil concentration and thus DPD phenotyping.Patients and methodsThe impact of renal function on uracilemia and DPD phenotype was studied on 3039 samples obtained from three French centers. We also explored the influence of dialysis and measured glomerular filtration rate (mGFR) on both parameters. Finally, using patients as their own controls, we assessed as to what extent modifications in renal function impacted uracilemia and DPD phenotyping.ResultsWe observed that uracilemia and DPD-deficient phenotypes increased concomitantly to the severity of renal impairment based on the estimated GFR, independently and more critically than hepatic function. This observation was confirmed with the mGFR. The risk of being classified 'DPD deficient' based on uracilemia was statistically higher in patients with renal impairment or dialyzed if uracilemia was measured before dialysis but not after. Indeed, the rate of DPD deficiency decreased from 86.4% before dialysis to 13.7% after. Moreover, for patients with transient renal impairment, the rate of DPD deficiency dropped dramatically from 83.3% to 16.7% when patients restored their renal function, especially in patients with an uracilemia close to 16 ng/ml.ConclusionsDPD deficiency testing using uracilemia could be misleading in patients with renal impairment. When possible, uracilemia should be reassessed in case of transient renal impairment. For patients under dialysis, testing of DPD deficiency should be carried out on samples taken after dialysis. Hence, 5-FU therapeutic drug monitoring would be particularly helpful to guide dose adjustments in patients with elevated uracil and renal impairment.

Project description:IntroductionIn April 2019, French authorities mandated dihydropyrimidine dehydrogenase (DPD) screening, specifically testing uracilemia, to mitigate the risk of toxicity associated with fluoropyrimidine-based chemotherapy. However, this subject is still of debate as there is no consensus on a standardized DPD deficiency screening test. We conducted a real-life retrospective study with the aim of assessing the impact of DPD screening on the occurrence of severe toxicity and exploring the potential benefits of complete genotyping using next-generation sequencing.MethodsAll adult patients consecutively treated with 5-fluorouracil (5-FU) or its oral prodrug at six cancer centers between March 2018 and February 2019 were considered for inclusion. Dihydropyrimidine dehydrogenase deficiency screening included gene encoding DPD (DPYD) genotyping using complete genome sequencing and DPD phenotyping (uracilemia or dihydrouracilemia/uracilemia ratio) or both tests. Associations between each DPD screening method and (i) severe (grade ≥3) early toxicity and (ii) fluoropyrimidine dose reduction in the second chemotherapy cycle were evaluated using multivariable logistic regression analysis. Furthermore, we assessed the concordance between DPD genotype and phenotype using Cohen's kappa.ResultsA total of 551 patients were included. Most patients were tested for DPD deficiency (86%) including DPYD genotyping only (6%), DPD phenotyping only (8%), or both (72%). Complete DPD deficiency was not detected in the study population. Severe early toxicity events were observed in 73 patients (13%), with two patients (0.30%) presenting grade 5 toxicity. Despite the numerically higher toxicity rate in untested patients, the occurrence of severe toxicity was not significantly associated with the DPD screening method (p = 0.69). Concordance between the DPD genotype and phenotype was weak (Cohen's kappa of 0.14).ConclusionDue to insufficient numbers, our study was not able to demonstrate any added value of DPYD genotyping using complete genome sequencing to prevent 5-FU toxicity. The optimal strategy for DPD screening before fluoropyrimidine-based chemotherapy requires further clinical evaluation.

Project description:Background and objectiveWhile standard doses of adjuvant fluoropyrimidine-based chemotherapies are generally safe for most patients, the risk of severe adverse drug reactions (ADRs) is increased for those with dihydropyrimidine dehydrogenase deficiency (DPYD), a genetic variation that affects drug metabolism. The objective of this study was to examine the cost effectiveness of offering DPYD pharmacogenetic-guided care, where genetic testing informs personalized dosing versus the current standard of care (SoC), which involves administering fluoropyrimidine-based therapies without prior genetic screening, for local or metastatic breast cancer patients in Qatar.MethodsWe developed a two-stage decision analysis, with an analytic tree model over a 6-month period, followed by a life-table Markov model over a lifetime horizon. We compared the current SoC with the alternate strategy of DPYD genetic screening in patients living in Qatar with local or metastatic breast cancer who were eligible for adjuvant fluoropyrimidine therapy. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were estimated from Hamad Medical Corporation, Qatar. The short-term outcome included the incremental cost-effectiveness ratio (ICER), defined as cost per success (survival without grade III/IV ADRs) at 6 months. The long-term outcome was the ICER, defined as cost per quality-adjusted life year (QALY) gained, with a 3% annual discount rate. The study adopted a public healthcare perspective in Qatar. Sensitivity analyses were conducted to explore the impact of key input parameters on the robustness of the model.ResultsIn the short-term model, at its base case, DPYD genomic screening was dominant over SoC with a mean cost-saving of QAR84,585 (95% confidence interval [CI], 45,270-151,657). This cost saving reflects the overall economic benefits associated with the implementation of DPYD genomic screening. In the long-term model, compared to the current SoC, DPYD genetic screening would result in an ICER of QAR21,107 (95% CI -59,382-145,664) per QALY gained.ConclusionBased on our model, implementing DPYD genetic screening to detect DPYD mutations in breast cancer patients before therapy initiation seems to be a cost-saving and cost-effective strategy in Qatar.

Dataset Information

DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

Background

Objectives

Methods

Findings

Conclusions

Publications

DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

Similar Datasets

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