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A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.

ABSTRACT: 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.

SUBMITTER: Tong CC

PROVIDER: S-EPMC6066555 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.

Tong Chi C CC Lam Ching W CW Lam Ka O KO Lee Victor H F VHF Luk Mai-Yee MY

Frontiers in oncology 20180724

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-ol ...[more]

PMID: 30087856

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Project description:Deficiency 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.Two-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.Among 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.Exploring 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.

Project description:IntroductionFluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD *2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence.Patient concernsA 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment.DiagnosisAfter few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0.InterventionsAs first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient's death.OutcomesAfter 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease.ConclusionsRecent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization.

Project description:Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

Dataset Information

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.

Publications

A Novel <i>DPYD</i> Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive <i>DPYD</i> Genotype Screening.

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