ABSTRACT
OBJECTIVES: Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway, with fewer than 40 patients published. Clinical findings are variable and some patients may remain asymptomatic. Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported. Here we present atrioventricular septal defect as a novel feature in dihydropyrimidinase deficiency. CASE PRESENTATION: A four-year-old male with global developmental delay, dysmorphic facies, autistic features and a history of seizures was diagnosed with dihydropyrimidinase deficiency based on strikingly elevated urinary dihydrouracil and dihydrothymine and a homozygous pathogenic nonsense variant in DPYS gene. He had a history of complete atrioventricular septal defect corrected surgically in infancy. CONCLUSIONS: This is the second report of congenital heart disease in dihydropyrimidinase deficiency, following a single patient with a ventricular septal defect. The rarity of the disease and the variability of the reported findings make it difficult to describe a disease-specific clinical phenotype. The mechanism of neurological and other systemic findings is unclear. Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits. We suggest that congenital heart disease may also be a rare phenotypic feature.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Heart Septal Defects , Humans , Male , Child, Preschool , Heart Septal Defects/genetics , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Prognosis , Developmental Disabilities/genetics , Developmental Disabilities/etiology , Developmental Disabilities/pathology , AmidohydrolasesABSTRACT
A DPD deficiency should be considered in case of severe toxicity even in the absence of common risk variants in DPYD.
Subject(s)
Antimetabolites, Antineoplastic , Capecitabine , Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Capecitabine/adverse effects , Dihydrouracil Dehydrogenase (NADP)/genetics , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Male , Female , Fatal Outcome , Middle AgedABSTRACT
Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Genotype , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Male , Female , Middle Aged , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Aged , Genotyping Techniques/methods , Adult , Fluorouracil/adverse effects , Fluorouracil/therapeutic useABSTRACT
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. METHODS: All adult patients consecutively treated with 5-fluorouracil (5-FU) or its oral prodrug at six cancer centers between March 2018 and February 2019 were considered for inclusion. Dihydropyrimidine dehydrogenase deficiency screening included gene encoding DPD (DPYD) genotyping using complete genome sequencing and DPD phenotyping (uracilemia or dihydrouracilemia/uracilemia ratio) or both tests. Associations between each DPD screening method and (i) severe (grade ≥3) early toxicity and (ii) fluoropyrimidine dose reduction in the second chemotherapy cycle were evaluated using multivariable logistic regression analysis. Furthermore, we assessed the concordance between DPD genotype and phenotype using Cohen's kappa. RESULTS: A total of 551 patients were included. Most patients were tested for DPD deficiency (86%) including DPYD genotyping only (6%), DPD phenotyping only (8%), or both (72%). Complete DPD deficiency was not detected in the study population. Severe early toxicity events were observed in 73 patients (13%), with two patients (0.30%) presenting grade 5 toxicity. Despite the numerically higher toxicity rate in untested patients, the occurrence of severe toxicity was not significantly associated with the DPD screening method (p = 0.69). Concordance between the DPD genotype and phenotype was weak (Cohen's kappa of 0.14). CONCLUSION: Due to insufficient numbers, our study was not able to demonstrate any added value of DPYD genotyping using complete genome sequencing to prevent 5-FU toxicity. The optimal strategy for DPD screening before fluoropyrimidine-based chemotherapy requires further clinical evaluation.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Adult , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydropyrimidine Dehydrogenase Deficiency/complications , Antimetabolites, Antineoplastic/therapeutic use , Retrospective Studies , Capecitabine , Genotype , FluorouracilABSTRACT
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. DPD is also important as the main enzyme in the catabolism of 5-fluorouracil (5-FU) which is extensively used as a chemotherapeutic agent. Even in the absence of clinical symptoms, individuals with either complete or partial DPD deficiency face a high risk of severe and even fatal fluoropyrimidine-associated toxicity. The identification of causative genetic variants in DPYD is therefore gaining increasing attention due to their potential use as predictive markers of fluoropyrimidine toxicity. METHODS: A male infant patient displaying biochemical features of DPD deficiency was investigated by clinical exome sequencing. Bioinformatics tools were used for data analysis and results were confirmed by MLPA and Sanger sequencing. RESULTS: A novel intragenic deletion of 71.2 kb in the DPYD gene was identified in homozygosity. The deletion, DPYD(NM_000110.4):c.850 + 23455_1128 + 8811del, eliminates exons 9 and 10 and may have resulted from a non-homologous end-joining event, as suggested by in silico analysis. CONCLUSIONS: The study expands the spectrum of DPYD variants associated with DPD deficiency. Furthermore, it raises the concern that patients at risk for fluoropyrimidine toxicity due to DPYD deletions could be missed during pre-treatment genetic testing for the currently recommended single nucleotide polymorphisms.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Infant , Humans , Male , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydrouracil Dehydrogenase (NADP)/metabolism , Antimetabolites, Antineoplastic/adverse effects , Fluorouracil/adverse effects , Genetic TestingABSTRACT
Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical 5-fluorouracil (5-FU) treatment in these patients, leading to inconsistent guideline recommendations for pretreatment testing and topical 5-FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary end point) and 1+ (secondary end point) toxicity was compared between DPYD variant carriers vs. wild-type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40, 95% confidence interval: 0.10-2.53, P = 0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5-FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5-FU treatment should be avoided in these patients.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Alleles , Retrospective Studies , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil , Dihydropyrimidine Dehydrogenase Deficiency/genetics , GenotypeABSTRACT
This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Neoplasms , Pharmacogenomic Testing , Humans , Cross-Sectional Studies , Health Personnel , Patient Acceptance of Health Care , Pharmacogenetics , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/geneticsABSTRACT
AIM: Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil [U], with U ≥ 16 µg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors. METHODS: Data from patients who underwent both phenotyping and genotyping were retrospectively collected. Complementary genetic analyses (genotyping of the variant c.557A>G and DPYD sequencing) were performed for patients with U ≥ 16 µg/L without any common variants. The characteristics of patients classified according to the congruence of the phenotyping and genotyping approaches were compared (Kruskal-Wallis test), and determinants of U levels were studied in the whole cohort (linear model). RESULTS: Among the 712 included patients, phenotyping and genotyping were discordant for 12.5%, with 63 (8.8%) having U ≥ 16 µg/L in the absence of a common variant. Complementary genetic investigations marginally reduced the percentage of discrepancies to 12.1%: Among the nine additional identified variants, only the c.557A>G variant, carried by three patients, had been previously reported to be associated with DPD deficiency. Liver dysfunction could explain certain discordances, as ASAT, ALP, GGT and bilirubin levels were significantly elevated, with more frequent liver metastases in patients with U ≥ 16 µg/L and the absence of a DPYD variant. The impact of cytolysis was confirmed, as ASAT levels were independently associated with increased U (p < 0.001). CONCLUSION: The frequent discordances between DPD phenotyping and genotyping approaches highlight the need to perform these two approaches to screen for all DPD deficiencies.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Genotype , Antimetabolites, Antineoplastic , Capecitabine , Retrospective Studies , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , FluorouracilABSTRACT
BACKGROUND: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. METHODS: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. RESULTS: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. CONCLUSIONS: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Humans , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Fluorouracil/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Retrospective Studies , Dihydrouracil Dehydrogenase (NADP)/genetics , EuropeABSTRACT
BACKGROUND: Fluoropyrimidines (FP) are among the most common class of prescribed anti-neoplastic drugs. This class has severe to moderate toxicity in around 10%-40% of those who take 5-fluorouracil (5-FU) or capecitabine for the treatment of cancer. In practice many patients with severe toxicities from FP use had dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. Several studies have proposed DPD screening before treatment with 5-fluorouracil (5-FU) and capecitabine or other drugs belonging to the FP group. This study aims to assess the level of awareness and attitudes of oncology specialists in Saudi Arabia toward genetic screening for DPD prior to giving FP. This highlights the importance of health guidelines required for implementation in our health care system, as a framework to adopt testing as a regular practice in clinical care. Based on the findings in this study, guidelines have been suggested for the Middle East North Africa region. METHODS: A cross-sectional survey study was conducted during 2021 targeting oncologists and clinical pharmacists working in the oncology departments across Saudi Arabia. RESULTS: A total of 130 oncologists and pharmacists completed the questionnaire representing a response rate of 87%. Most of the respondents indicated that they prescribe FP in clinical practice, but 41% of respondents reported that they have never ordered a specific molecular test during their practice. Only 20% of respondents reported that they often screen for DPD deficiency prior to prescribing FP. Significantly higher rates of awareness of potential dihydropyrimidine dehydrogenase gene (DPYD) mutation were observed among respondents in governmental hospitals (81.1% vs. 47.4% in private hospitals), and among those with more years of practice (80.6% if 5 or more years of practice vs. 59.3% if less than 5 years of practice). Also, higher rates of observing the impact of DPD testing were present among respondents with a PharmD (35% vs. 11% for oncologists and 18% for other professions) and among those with 5 or more years of practice (24.6% vs. 7.7% among those with less than 5 years). CONCLUSION: While in some institutions there is a high level of awareness among oncology specialists in Saudi Arabia regarding the effect of the potentially serious DPD enzyme deficiency as a result of gene mutations, screening for these mutations prior to prescribing FP is not a routine practice in hospitals across the country. The findings of this study should promote personalized medicine with recognition of interpatient variability via DPD testing to manage the risks of FP prescribing more effectively in the Kingdom of Saudi Arabia.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Capecitabine/adverse effects , Antimetabolites, Antineoplastic/adverse effects , Saudi Arabia , Cross-Sectional Studies , Fluorouracil/adverse effects , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Dihydropyrimidine Dehydrogenase Deficiency/geneticsABSTRACT
BACKGROUND: In 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 METHODS: Two 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. RESULTS: The 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%). CONCLUSIONS: We 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.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Gastrointestinal Neoplasms , Humans , Antimetabolites, Antineoplastic/adverse effects , Capecitabine/adverse effects , Denmark , Dihydropyrimidine Dehydrogenase Deficiency/chemically induced , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , Gastrointestinal Neoplasms/drug therapy , Genotype , Uracil/therapeutic useABSTRACT
Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Humans , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Fluorouracil , Antimetabolites, Antineoplastic/therapeutic use , Capecitabine , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydrouracil Dehydrogenase (NADP)/metabolismABSTRACT
Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.
Subject(s)
Antimetabolites, Antineoplastic , Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Fluorouracil , Pharmacogenomic Variants , Humans , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/toxicity , Capecitabine/adverse effects , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil/adverse effects , Fluorouracil/toxicity , GenotypeABSTRACT
Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype−phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype−phenotype association data is needed to enable the clinical use of sequencing data.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydrouracil Dehydrogenase (NADP)/metabolism , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Fluorouracil/adverse effects , Fluorouracil/metabolism , Floxuridine , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/metabolism , ExonsABSTRACT
Measuring uracil (U) levels in plasma is a convenient surrogate to establish dihydropyrimidine dehydrogenase (DPD) status in patients scheduled with 5-fluorouracil (5-FU) or capecitabine. To what extent renal impairment could impact on U levels and thus be a confounding factor is a rising concern. Here, we report the case of a cancer patient with severe renal impairment scheduled for 5-FU-based regimen. Determination of his DPD status was complicated because of his condition and the influence of intermittent haemodialysis when monitoring U levels. The patient was initially identified as markedly DPD-deficient upon U measurement (i.e., U = 40 ng/mL), but further monitoring between and immediately after dialysis showed mild deficiency only (i.e., U = 34 and U = 19 ng/mL, respectively). Despite this discrepancy, a starting dose of 5-FU was cut by 50% upon treatment initiation. Tolerance was good and 5-FU dosing was next shifted to 25% reduction, then further shifted to normal dosing at the 5th course, with still no sign for drug-related toxicities. Further DPYD genotyping showed none of the four allelic variants usually associated with loss of DPD activity. Of note, the excellent tolerance upon standard dosing strongly suggests that this patient was actually not DPD-deficient, despite U values always above normal concentrations. This case report highlights how critical is the information regarding the renal function of patients with cancer when phenotyping DPD using U plasma as a surrogate, and that U accumulation in patients with such condition is likely to yield false-positive results.
Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Neoplasms , Renal Insufficiency , Antimetabolites, Antineoplastic/adverse effects , Capecitabine , Dihydropyrimidine Dehydrogenase Deficiency/complications , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil/therapeutic use , Humans , Neoplasms/drug therapy , Renal Insufficiency/complications , Renal Insufficiency/etiology , Uracil/therapeutic useABSTRACT
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. METHODS: We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping. RESULTS: Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations. CONCLUSION: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.
Subject(s)
Colonic Neoplasms , Dihydropyrimidine Dehydrogenase Deficiency , Capecitabine/adverse effects , Chemotherapy, Adjuvant , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Cost-Benefit Analysis , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil/adverse effects , Genotype , HumansABSTRACT
Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.
Subject(s)
Deoxycytidine , Dihydropyrimidine Dehydrogenase Deficiency , Dihydrouracil Dehydrogenase (NADP) , Urinary Bladder Neoplasms , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Dihydropyrimidine Dehydrogenase Deficiency/drug therapy , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , Genomics/methods , Humans , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , GemcitabineABSTRACT
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. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.