Challenges in DPYD Test Implementation in Patients Treated with Fluoropyrimidines are DPYD Genotype Arriving on Time? [Letter].
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SUBMITTER: Lopez Lopez-Cepero M
PROVIDER: S-EPMC10758252 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
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Challenges in DPYD Test Implementation in Patients Treated with Fluoropyrimidines are DPYD Genotype Arriving on Time? [Letter].
López López-Cepero Marta M Obrador de Hevia Antonia A Guillot Morales Mónica M
Pharmacogenomics and personalized medicine 20231228
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Project description:Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD). Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy. Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.
| S-EPMC6066555 | biostudies-literature
Project description:Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.
| S-EPMC10226670 | biostudies-literature
Project description:PurposeMetastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London.MethodsWe reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity.ResultsSixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar-plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity.ConclusionsProspective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.
| S-EPMC6533219 | biostudies-literature
Project description:Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.
| S-EPMC7080718 | biostudies-literature
Project description:Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.
| S-EPMC8401253 | biostudies-literature
Project description:Background5-Fluorouracil (5-FU) and capecitabine are fluoropyrimidine derivatives that mainly metabolized with dihydropyrimidine dehydrogenase enzyme (DPD). The genetic polymorphism in the genes encoding this enzyme may result in a decrease or loss of enzyme activity which may lead to the accumulation of medicines, their metabolites and potential toxicity.MethodThis cross-sectional study was conducted on 88 participants with colorectal cancer (CRC). After DNA extraction, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the DPD gene (DPYD) polymorphisms including IVS 14 + 1 G > A, 2846 A > T and 2194 G > A. Chemotherapy-induced side effects were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE Version 5.0).ResultData were collected from 227 chemotherapy cycles of 88 patients with CRC. In a comparison of FOLFOX and FOLFIRI regimens, there was no significant difference in the occurrence of chemotherapy-induced diarrhea, nausea, vomiting and oral mucositis. However, the peripheral neuropathy was more frequent in patients who were treated with FOLFOX (P < 0.001) and hair loss was more common in patients who received FOLFIRI regimen (P = 0.048). Incidence of the DPD IVS14 + 1 G > A polymorphism was observed in four patients (5.5%). There was no association between IVS14 + 1 G > A polymorphism and the occurrence of adverse reactions.ConclusionFOLFOX and FOLFIRI were the most common regimens in CRC patients and their toxicity profile was different in some adverse reactions. Prevalence of IVS14 + 1G > A variant was relatively higher than other similar studies.Trial registrationApproval code; IR.MAZUMS.REC.95.2480.
| S-EPMC7298798 | biostudies-literature
Project description:RationaleScreening and treating newly arriving immigrants for latent tuberculosis infection (LTBI) in low-incidence countries could be promising to reduce the tuberculosis incidence among this population. The effectiveness of screening with the tuberculin skin test (TST) is unknown.ObjectivesTo estimate the risk of progression to tuberculosis within two years after entry, stratified by TST result at entry.MethodsIn a case-base design, we determined the prevalence of TST positives (10 mm and 15 mm) among a representative cohort of immunocompetent immigrants (n?=?643) aged ?18 years who arrived between April 2009 and March 2011 in The Netherlands (base cohort). Immigrants who progressed to tuberculosis within two years after arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register (case source cohort). The prevalence of TST positives from the base cohort was projected on the case source cohort to estimate the risk of progression to active tuberculosis by using bayesian analyses to adjust for the sensitivity of the TST and Poisson regression analyses to take into account the random error of the number of extracted cases.ResultsThe prevalence of TST positives was 42% and 23% for a cut-off value of 10 mm and 15 mm, respectively. The overall risk of progression to tuberculosis if TST positive was 238 per 100,000 population (95% CI 151-343) and 295 per 100,000 population (95% CI 161-473) for a cut-off value of ?10 mm and ?15 mm, respectively. The corresponding risk for TST negatives was 19 (95% CI 0-59) and 58 (95% CI 25-103).ConclusionThe TST has the discriminatory ability to differentiate between individuals at low and high risk of disease.
| S-EPMC3609741 | biostudies-literature
Project description:BackgroundDihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom.MethodsPatients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers.ResultsBetween 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924).ConclusionsOur study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.
| S-EPMC10131438 | biostudies-literature
Project description:BackgroundDeficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.MethodsTwo-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.ResultsAmong the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3-4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.ConclusionsExploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.
| S-EPMC5421769 | biostudies-literature
Project description:BackgroundIn 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping.Patients and methodsTwo hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank.ResultsThe frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%).ConclusionsWe found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.
| S-EPMC10024141 | biostudies-literature