Influence of DPYD gene polymorphisms on 5-Fluorouracil toxicities in Thai colorectal cancer patients.

DPYD polymorphisms have been widely found to be related to 5-FU-induced toxicities. The aim of this study was to establish significant associations between five single-nucleotide polymorphisms of DPYD and 5-FU hematological toxicities in Thai colorectal cancer patients. The toxicities were analyzed at the first and second cycles of 5-FU administration in 75 patients.

The impact of diet induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.

Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1).

DPYD genotype-guided dose personalisation for fluoropyrimidine-based chemotherapy prescribing in solid organ cancer patients in Australia: GeneScreen 5-FU study protocol.

Background: Fluoropyrimidine (FP) chemotherapies are commonly prescribed for upper and lower gastrointestinal, breast and head and neck malignancies. Over 16,000 people with cancer require FP chemotherapies per annum in Australia. Between 10 and 40% patients experience grade 3-4 (≥ G3) toxicities that require hospital-based management ± intensive care admission.

Large-Scale Pharmacogenomics Analysis of Patients With Cancer Within the 100,000 Genomes Project Combining Whole-Genome Sequencing and Medical Records to Inform Clinical Practice.

Purpose: As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service.

Methods: Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (, , , ) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants.

Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients.

Although the risk of fluoropyrimidine toxicity may be decreased by identifying poor metabolizers with a preemptive dihydropyrimidine dehydrogenase () test, following international standards, many patients with wild-type (WT) genotypes for classic variations may still exhibit adverse drug reactions (ADRs). Therefore, the safety of fluoropyrimidine therapy could be improved by identifying new polymorphisms associated with ADRs. This study was carried out to assess whether testing for the underestimated c.

Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.

Gene Polymorphism Modifies the Effect of Common Gene Variants on Severe Toxicity in Patients with Gastrointestinal Tumors Treated with Fluoropyrimidine-Based Anticancer Therapy.

To reduce severe fluoropyrimidine-related toxicity, pharmacogenetic guidelines recommend a dose reduction for carriers of four high-risk variants in the gene (*2A, *13, c.2846A>T, HapB3). The polymorphism in the gene has been shown to enhance the predictive value of these variants.

Clinical Implementation of Rare and Novel Variants for Personalizing Fluoropyrimidine Treatment: Challenges and Opportunities.

Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (, c.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

Purpose: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption.

Evaluation of early fluoropyrimidine toxicity in solid organ cancer patients: a retrospective observational study in Australia.

Background: Despite common global usage, fluoropyrimidine (FP; 5-flurouracil and capecitabine)-related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3-5 FP-related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death).

Aims: This retrospective audit evaluated Grades 3-5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter-New England Local Health District from June 2020 to June 2022.

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase () Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

Purpose: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain genetic variants with standard dosing. We implemented genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization.

Methods: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five variants as standard practice per provider discretion.

DPYD genetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: a systematic review.

Background: Pre-treatment DPYD screening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. Four DPYD gene variants which are more prominently found in Europeans are tested.

Methods: Our systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023.

Lethal Capecitabine Toxicity in Patients With Complete Dihydropyrimidine Dehydrogenase Deficiency Due to Ultra-Rare Variants.

A DPD deficiency should be considered in case of severe toxicity even in the absence of common risk variants in DPYD.

Capecitabine-induced severe adverse events-therapeutic drug monitoring and -gene analysis are recommended.

In this report, two cases of patients with severe adverse events after an adjuvant treatment with capecitabine are described in detail. The first patient suffered from a severe ileocolitis, where ultimately intensive care treatment, total colectomy and ileum resection was necessary. The second patient experienced a toxic enteritis, which could be managed conservatively.

Design and Implementation of an Opt-Out, End-to-End, Preemptive Testing Program for Patients Planned for a Systemic Fluoropyrimidine.

Purpose: Several allelic variants of the gene encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine.

Methods: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education.

A novel large intragenic DPYD deletion causing dihydropyrimidine dehydrogenase deficiency: a case report.

Background: Dihydropyrimidine dehydrogenase (DPD), is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. Deleterious variants in the DPYD gene cause DPD deficiency, a rare autosomal recessive disorder. The clinical spectrum of affected individuals is wide ranging from asymptomatic to severely affected patients presenting with intellectual disability, motor retardation, developmental delay and seizures.

Complete DPYD genotyping combined with dihydropyrimidine dehydrogenase phenotyping to prevent fluoropyrimidine toxicity: A retrospective study.

Introduction: In 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.

Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.

Background: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations.

Diversity of oncopharmacogenetic profile within Spanish population.

Consensus guidelines for genotype-guided fluoropyrimidine dosing based on variation in the dihydropyrimidine dehydrogenase (DPYD) gene before treatment have been firmly established. The prior pharmacogenetic report avoids the serious toxicity that inevitably occurred in a non-negligible percentage of the treated patients. The precise description of the allelic distribution of the variants of interest in our reference populations is information of great interest for the management of the prescription of these antineoplastic drugs.

rs895819 TC genotype increases risk of fluoropyrimidine-induced severe toxicity independently of variations.

MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients.