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Introduction: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital., Methods: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 ( n  = 197), and those starting first-line treatment in May 2019-April 2020 ( n  = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants., Results: In those treated 2020-2021, cancer subtypes included colorectal ( n  = 120, 61%), breast ( n  = 34, 17%), and biliary/pancreatic cancers ( n  = 21, 11%). Median patient age was 62 (range 25-86 years); 40% ( n  = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% ( n  = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening., Discussion: Other Irish studies estimated prevalence at 11-12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence., Conclusions: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients., Competing Interests: Authors contributionRK designed the study, analysed the data and wrote the manuscript, TM, AAlF and AC collected data and proofread the manuscript, CM assisted with data analysis and manuscript editing, JmC was the principal investigator, responsible for study oversight and manuscript editing and approval. All authors reviewed and approved the final version of the manuscript. Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: Treatment with dihydropyrimidines poses a significant risk of serious adverse reactions for patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This study seeks to analyse the correlation between DPD deficiency and plasmatic uracil values in patients who are candidates for a fluoropyrimidine scheme. It also studies the incidence of adverse events (AEs) in patients with DPD deficiency established with plasmatic uracil determination., Methods: This was a retrospective observational study conducted in a tertiary level establishment from September 2020 to April 2021. Patients included were diagnosed with gastrointestinal tumours, were of good status, and were initiated into a fluoropyrimidine-based regimen. The incidence and grade of AEs, according Common Terminology Criteria for Adverse Events (CTCAE), were collected and compared in patients with and without DPD deficiency., Results: 119 patients diagnosed with gastrointestinal cancer met the inclusion criteria. In 92 (77%) patients there was no DPD deficiency according to plasmatic uracil thresholds. In the group of patients without deficit, dose reductions oscillated between 10-25% (mean 17.4%). In the no DPD deficiency group, 43 (46%) patients experienced AEs. Patients who had a DPD deficiency according to plasmatic uracil measurements were started on a 5-fluorouracil (5-FU) regimen with a dose reduction of 15-50% (mean 35%). In this group, 12 patients (44%) experienced some AEs., Conclusion: New research is needed to clarify the correlation between plasma uracil values and DPD deficiency to achieve an optimal balance between clinical benefit and toxicity., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD-deficient patients remains elusive., Methods: Among a nationwide cohort of 5886 phenotyped patients with cancer who were screened for DPD deficiency over a 3 years period, we assessed the characteristics of both DPD phenotypes and DPYD genotypes in a subgroup of 3680 patients who had completed the two tests. The extent to which defective allelic variants of DPYD predict DPD activity as estimated by the plasma concentrations of uracil [U] and its product dihydrouracil [UH 2 ] was evaluated., Results: When [U] was used to monitor DPD activity, 6.8% of the patients were classified as having DPD deficiency ([U] > 16 ng/ml), while the [UH 2 ]:[U] ratio identified 11.5% of the patients as having DPD deficiency (UH 2 ]:[U] < 10). [U] classified two patients (0.05%) with complete DPD deficiency (> 150 ng/ml), and [UH 2 ]:[U] < 1 identified three patients (0.08%) with a complete DPD deficiency. A defective DPYD variant was present in 4.5% of the patients, and two patients (0.05%) carrying 2 defective variants of DPYD were predicted to have low metabolism. The mutation status of DPYD displayed a very low positive predictive value in identifying individuals with DPD deficiency, although a higher predictive value was observed when [UH 2 ]:[U] was used to measure DPD activity. Whole exon sequencing of the DPYD gene in 111 patients with DPD deficiency and a "wild-type" genotype (based on the four most common variants) identified seven heterozygous carriers of a defective allelic variant., Conclusions: Frequent genetic DPYD variants have low performances in predicting partial DPD deficiency when evaluated by [U] alone, and [UH 2 ]:[U] might better reflect the impact of genetic variants on DPD activity. A clinical trial comparing toxicity rates after dose adjustment according to the results of genotyping or phenotyping testing to detect DPD deficiency will provide critical information on the best strategy to identify DPD deficiency.

5-fluorouracil (5-FU) and its prodrug capecitabine are one of the most commonly used chemotherapeutic drugs. DPD-deficient cancer patients may be at risk of severe and sometimes lethal toxicity after the administration of 5-FU. In 39-61% of the cases severe toxicity of 5-FU is caused by decreased DPD acivity. DPD is the initial and rate-limiting enzyme of the metabolism of pyrimidines. 80-90% of the administered 5-FU is catabolised by DPD. Mutation of the DPYD gene encoding DPD result in decreased enzyme activity--total (0.2% of population) or partial (3-5% of population). Determination of DPD activity can be used as a screening procedure to identify patients with a DPD deficiency, before the start of treatment with 5-FU. There are several methods for DPD activity determination: the detection of relevant DPYD gene single-nucleotide polymorphism (SNPs), measurement of the level of DPYDmRNA expression, the evaluation of DPD activity in PBMC, the measurement of uracil in plasma and urea, evaluation of the UH2/U (dihydrouracil/uracil) and THYH2/THY (dihydrothymine/tymine) ratio in plasma and urea, [2-C13]uracil breath test, the analysis of fluorouracil and dihydrofluorouracil in plasma after administered a test dose of fluorouracil and measurement of 2-fluoro-beta-alanine. So far more than 30 mutations of DPYD gene have been identified in patients with cancer. A large number of them limits introduction of simple genetic test, which could be used for detection of DPD deficiency. Therefore scientists in searching of the simplest, the cheapest and the most available technique for detection DPD deficiency, generally use methods associated with measurement of DPD activity.

Dihydropyrimidine dehydrogenase enzyme (DPD) deficiency is a pharmacogenetic syndrome leading to severe side-effects in patients receiving therapies containing the anticancer drug 5-fluorouracil (5-FU). The aim of this population study is to evaluate gene variations in the coding region of the dihydropyrimidine dehydrogenase gene (DPYD) in the Tunisian population. One hundred and six unrelated healthy Tunisian volunteers were genotyped by denaturing HPLC (DHPLC). Twelve variants in the coding region of the DPYD were detected. Allele frequencies of DPYD*5 (A1627G), DPYD*6 (G2194A), DPYD*9A (T85C), A496G, and G1218A were 12.7%, 7.1%, 13.7%, 5.7%, and 0.5%, respectively. The DPYD alleles DPYD*2A (IVS 14+1g>1), DPYD*3 (1897 del C) and DPYD*4 (G1601A) associated with DPD deficiency were absent from the examined subjects. We describe for the first time a new intronic polymorphism IVS 6-29 g>t, found in an allelic frequency of 4.7% in the Tunisian population. Comparing our data with that obtained in Caucasian, Egyptian, Japanese and African-American populations, we found that the Tunisian population resembles Egyptian and Caucasian populations with regard to their allelic frequencies of DPYD polymorphisms. This study describes for the first time the spectrum of DPYD sequence variations in the Tunisian population.