271 results match your criteria Fluorouracil Toxicity and DPYD


Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer.

Clin Colorectal Cancer 2022 May 11. Epub 2022 May 11.

Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center/Geisel School of Medicine, Lebanon, NH; The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine, Lebanon, NH.

Background: Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States. Read More

View Article and Full-Text PDF

Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping.

Clin Pharmacol Ther 2022 May 23. Epub 2022 May 23.

School of Medicine and Public Health, University of Newcastle, College of Health, Medicine and Wellbeing, Callaghan, New South Wales, Australia.

Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Read More

View Article and Full-Text PDF

Can upfront DPYD extended variant testing reduce toxicity and associated hospital costs of fluoropyrimidine chemotherapy? A propensity score matched analysis of 2022 UK patients.

BMC Cancer 2022 Apr 26;22(1):458. Epub 2022 Apr 26.

Oxford University Hospitals NHS Trust, Oxford, UK.

Aim: To independently assess the impact of mandatory testing using an extended DPYD variant panel (ToxNav®) and consequent dose adjustment of Capecitabine/5-FU on recorded quantitative toxicity, symptoms of depression, and hospital costs.

Methods: We used propensity score matching (PSM) to match 466 patients tested with ToxNav® with 1556 patients from a historical cohort, and performed regression analysis to estimate the impact of ToxNav®on toxicity, depression, and hospital costs.

Results: ToxNav® appeared to reduce the likelihood of experiencing moderate (OR: 0. Read More

View Article and Full-Text PDF

Frequency and clinical relevance of DPYD genetic variants in gastrointestinal cancer patients.

Farm Hosp 2021 12 21;45(7):5-10. Epub 2021 Dec 21.

Pharmacy Department, Hospital de la Santa Creu i Sant Pau, Barcelona. Spain..

Objective: To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the  implementation of a multidisciplinary circuit at three months from its  implementation.

Method: This is a descriptive, observational and retrospective study, which  included adult patients with gastrointestinal cancer treated at a tertiary  university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The  variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity  developed during the first three cycles. Read More

View Article and Full-Text PDF
December 2021

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

Br J Cancer 2022 Mar 19. Epub 2022 Mar 19.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.

Background: Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type). Read More

View Article and Full-Text PDF

Survey of US Medical Oncologists' Practices and Beliefs Regarding Testing Before Fluoropyrimidine Chemotherapy.

JCO Oncol Pract 2022 06 3;18(6):e958-e965. Epub 2022 Mar 3.

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI.

Purpose: Patients who carry reduced-activity polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment testing and understand the factors deterring oncologists from ordering testing. Read More

View Article and Full-Text PDF

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing.

Cancer 2022 Apr 28;128(8):1649-1657. Epub 2022 Jan 28.

Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois.

Background: In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. Read More

View Article and Full-Text PDF

Treating patients with dihydropyrimidine dehydrogenase (DPD) deficiency with fluoropyrimidine chemotherapy since the onset of routine prospective testing-The experience of a large oncology center in the United Kingdom.

Semin Oncol 2022 04 13;49(2):170-177. Epub 2021 Dec 13.

Royal Surrey County Hospital, Guildford, Surrey, United Kingdom.

Background: Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0. Read More

View Article and Full-Text PDF

Clinical Relevance of Novel Polymorphisms in the Dihydropyrimidine Dehydrogenase () Gene in Patients with Severe Fluoropyrimidine Toxicity: A Spanish Case-Control Study.

Pharmaceutics 2021 Nov 29;13(12). Epub 2021 Nov 29.

Clinical Pharmacology Department, La Princesa University Hospital, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.

Among cancer patients treated with fluoropyrimidines, 10-40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase () gene may reduce DPD function, the main enzyme responsible for the metabolism of fluoropyrimidines. This leads to drug accumulation and to an increased risk of toxicity. Read More

View Article and Full-Text PDF
November 2021

A narrative review of genetic factors affecting fluoropyrimidine toxicity.

Precis Cancer Med 2021 Dec 30;4. Epub 2021 Dec 30.

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Objective: Our objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation.

Background: FPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0. Read More

View Article and Full-Text PDF
December 2021

Frequency of DPYD gene variants and phenotype inference in a Southern Brazilian population.

Ann Hum Genet 2022 03 13;86(2):102-107. Epub 2021 Dec 13.

Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Fluoropyrimidines are chemotherapy drugs that may cause severe adverse events, and their metabolism occurs by dihydropyrimidine deydrogenase (DPD), coded by DPYD. Variants in the DPYD were associated to a greater risk of toxicity. Our aim was to determine the frequency of the most relevant DPYD alleles according to CPIC guidelines (DPYD*2A-rs3918290, DPYD*13-rs55886062, rs67376798, and HapB3-rs75017182) in a sample of 800 healthy Southern Brazilians. Read More

View Article and Full-Text PDF

Genetic polymorphisms on the effectiveness or safety of breast cancer treatment: Clinical relevance and future perspectives.

Mutat Res Rev Mutat Res 2021 Jul-Dec;788:108391. Epub 2021 Jul 17.

Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Granada, Spain. Electronic address:

Breast cancer (BC) is the most frequent neoplasm and one of the main causes of death in women. The pharmacological treatment of BC consists of hormonal therapy, chemotherapeutic agents and targeted therapy. The response to BC therapy is highly variable in clinical practice. Read More

View Article and Full-Text PDF
December 2021

Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients.

N Z Med J 2021 11 12;134(1545):120-128. Epub 2021 Nov 12.

Medical Oncologist, Department of Oncology, Canterbury District Health Board & Department of Medicine, University of Otago, Christchurch, New Zealand.

Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. Read More

View Article and Full-Text PDF
November 2021

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.

Clin Transl Oncol 2022 Mar 13;24(3):483-494. Epub 2021 Nov 13.

Clinical Pharmacology Service, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Sociedad Española de Farmacogenética y Farmacogenómica (SEFF), C/Diego de León, 62., 28006, Madrid, Spain.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. Read More

View Article and Full-Text PDF

Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes.

Cancers (Basel) 2021 Sep 8;13(18). Epub 2021 Sep 8.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.

The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Read More

View Article and Full-Text PDF
September 2021

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BMC Cancer 2021 Sep 16;21(1):1030. Epub 2021 Sep 16.

Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.

Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0. Read More

View Article and Full-Text PDF
September 2021

Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis.

Oncologist 2021 12 29;26(12):1008-1016. Epub 2021 Sep 29.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.

Background: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants.

Materials And Methods: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c. Read More

View Article and Full-Text PDF
December 2021

Genotyping in Patients Who Have Planned Cancer Treatment With Fluoropyrimidines: A Health Technology Assessment.

Authors:

Ont Health Technol Assess Ser 2021 12;21(14):1-186. Epub 2021 Aug 12.

Background: Fluoropyrimidine drugs (such as 5-fluorouracil and capecitabine) are used to treat different types of cancer. However, these drugs may cause severe toxicity in about 10% to 40% of patients. A deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the gene, increases the risk of severe toxicity. Read More

View Article and Full-Text PDF
October 2021

Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

J Pers Med 2021 Aug 13;11(8). Epub 2021 Aug 13.

Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain.

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 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. Read More

View Article and Full-Text PDF

Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes.

Therap Adv Gastroenterol 2021 3;14:17562848211024464. Epub 2021 Jul 3.

Tufts Medical Center, Boston, MA, USA.

Background: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase ( and thymidylate synthetase (), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. Read More

View Article and Full-Text PDF

Use of Uridine Triacetate to Reverse Severe Persistent Myelosuppression Following 5-fluorouracil Exposure in a Patient With a c.557A>G Heterozygous DPYD Variant.

Clin Colorectal Cancer 2021 09 6;20(3):273-278. Epub 2021 Apr 6.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Electronic address:

View Article and Full-Text PDF
September 2021

DPYD variant testing in candidates for fluoropyrimidine treatment: A study protocol.

Farm Hosp 2021 Apr 15;45(3):155-159. Epub 2021 Apr 15.

Department of Pharmacy, Virgen Macarena University Hospital, Sevilla, Spain..

Objective: The main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by  comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one  will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive  effect. Read More

View Article and Full-Text PDF

Role of microRNAs in fluoropyrimidine-related toxicity: what we know.

Eur Rev Med Pharmacol Sci 2021 04;25(8):3306-3315

"Prof. Dr. Ion Chiricuţă" Oncology Institute, Cluj-Napoca, Romania.

Although more than half a century has passed since the discovery of fluoropyrimidines, they are still used in the treatment of many types of cancer, and it is estimated that annually two million patients undergo fluoropyrimidine-based chemotherapy. The toxicity resulting from the use of fluoropyrimidines affects about 30-40% of patients, which in some cases may prove to be lethal. The key player in fluoropyrimidine toxicity is DPD activity, and patients with deficits are more likely to develop significant adverse events. Read More

View Article and Full-Text PDF

An Evaluation of the Diagnostic Accuracy of a Panel of Variants in and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK.

Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110. Read More

View Article and Full-Text PDF

Potential Impact of Variation on Fluoropyrimidine Drug Response in sub-Saharan African Populations.

Front Genet 2021 9;12:626954. Epub 2021 Mar 9.

Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.

Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase () gene. Read More

View Article and Full-Text PDF

Near Miss or Standard of Care? Screening for Cancer Patients Receiving Fluorouracil.

Curr Oncol 2020 12 18;28(1):94-97. Epub 2020 Dec 18.

London Health Sciences Centre and Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the gene, and variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. Read More

View Article and Full-Text PDF
December 2020

Comparison of a thymine challenge test and endogenous uracil-dihydrouracil levels for assessment of fluoropyrimidine toxicity risk.

Cancer Chemother Pharmacol 2021 05 9;87(5):711-716. Epub 2021 Mar 9.

Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Purpose: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity. Read More

View Article and Full-Text PDF

Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Clin Transl Sci 2021 07 23;14(4):1338-1348. Epub 2021 Feb 23.

Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Read More

View Article and Full-Text PDF

Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: Implication for 5-fluorouracil toxicity.

Br J Clin Pharmacol 2021 08 30;87(8):3234-3243. Epub 2021 Mar 30.

Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, INO-F, Bern, Switzerland.

Aims: The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy.

Methods: Plasma dihydrouracil/uracil (UH /U) ratios were measured as a population marker for DPD activity in a total of 1382 subjects from 4 independent studies. Genotype and haplotype correlations with UH /U ratios were assessed. Read More

View Article and Full-Text PDF

Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur).

Acta Clin Belg 2022 Apr 11;77(2):346-352. Epub 2021 Jan 11.

Department of Gastroenterology, UZ Gent, Gent.

Objectives: Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Read More

View Article and Full-Text PDF