Prevalence of DPYD gene mutations among patients receiving 5-FU therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 447-447
Author(s):  
Jennifer Saam ◽  
Karla Bowles ◽  
Laurie Korst ◽  
Kendel Kline ◽  
Benjamin Roa ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Gene Mutations ◽  
European Ancestry ◽  
Severe Toxicity ◽  
Sequencing Data ◽  
Dpyd Gene ◽  
Commercial Laboratory ◽  
Gene Testing ◽  
Exposure Levels ◽  
Grade 3

447 Background: Dihydropyrimidine dehydrogenase (DPYD) is the major enzyme that metabolizes 5-Fluoruracil (5-FU), a component of many chemotherapy regimens. Patients with a DPYD gene mutation have higher 5-FU plasma levels, leading to a 50-60% risk of a grade 3-4 toxicity. DPYD mutations have an estimated prevalence of 3-5% in the general population, but full sequencing is rarely performed in published studies. Analyses of the largest set of full DPYD gene sequencing test results from a commercial laboratory database are presented. Methods: A set of 3,083 patients was analyzed. Patient demographics (age, gender, ethnicity) and pre-test grade 3-4 toxicity status (none, 5-FU related, other) were obtained from the test request form. Descriptive analyses were performed to estimate mutation prevalence overall, and by toxicity and ancestry classifications, as well as to characterize mutations of interest. A subset of 24 patients tested for DPYD mutations in response to high 5-FU exposure levels was also analyzed. Results: The overall DPYD mutation prevalence was 7.3%. Mutations were present in 4.7% and 10.3% of patients experiencing none and at least one 5-FU related toxicity pre-test, respectively. Among patients with toxicities pre-test, the prevalence increased from 7.8% to 31.6% for those experiencing a single to all four toxicity types. Among 5-FU related toxicities, mutation prevalence was highest (18.5%) for hematopoietic events. The previously reported founder mutation IVS14+1G>A had a relative prevalence 42.7%, but 30.9% of these mutations were seen in patients not reporting a Western/Northern European ancestry. Among the subset of patients with high 5-FU exposure levels, 29% had a DPYD mutation showing a genetic causality. Conclusions: 5-FU in chemotherapy regimens remains widespread, yet DPYD gene testing utilization remains minimal. Most testing occurs post-treatment in response to a severe toxicity rather than pre-treatment, which would permit physicians to adapt treatment and reduce toxicity risk. Compared to previous studies, this study using full sequencing data from 3083 patients provides robust estimates of DPYD mutation prevalence and helps characterize DPYD mutations of particular interest.

Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18644-e18644
Author(s):  
Benjamin Lee ◽  
Sarah Glewis ◽  
Marliese Alexander ◽  
Danny Rischin ◽  
Prudence A. Francis ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Program Implementation ◽  
Dihydropyrimidine Dehydrogenase ◽  
European Medicines Agency ◽  
Buccal Swab ◽  
Dpyd Gene ◽  
Testing Service ◽  
Gene Testing ◽  
Timely Access ◽  
Grade 3

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G > A, c.1679T > G, c.2846A > T, c.1236G > A and c.557A > G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA.

Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 521-521
Author(s):  
Moh'd M. Khushman ◽  
Peter Joel Hosein ◽  
Daniel Cameron ◽  
David Roland Clarkson ◽  
Thomas Wayne Butler ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Single Nucleotide ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Dpyd Gene ◽  
Gene Testing ◽  
Grade 3 ◽  
Dose Limiting Toxicity

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.

scholarly journals Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581880304 ◽  
Author(s):  
Con Murphy ◽  
Stephen Byrne ◽  
Gul Ahmed ◽  
Andrew Kenny ◽  
James Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cost Savings ◽  
Cost Effective ◽  
Public Hospitals ◽  
Severe Toxicity ◽  
Care Payer ◽  
Input Variables ◽  
Grade 3 ◽  
The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

scholarly journals Tegafur–uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle

2012 ◽  
Vol 4 (4) ◽  
pp. 167-172 ◽  
Author(s):  
Daniel I.G. Cubero ◽  
Felipe Melo Cruz ◽  
Patrícia Santi ◽  
Ismael Dale C.G. Silva ◽  
Auro del Giglio
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Dehydrogenase Deficiency ◽  
Dihydropyrimidine Dehydrogenase ◽  
Gene Sequencing ◽  
Severe Toxicity ◽  
Safe Alternative ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Proof Of Principle

Objective: The objective of this study was to evaluate the safety of using tegafur–uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. Patients and Methods: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m2/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. Results: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Conclusion: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.

scholarly journals Predictive Value of Clinical Toxicities to Chemotherapy with Fluoropyrimidines and Oxaliplatin in Colorectal Cancer by DPYD and GSTP1 Genes Polymorphisms

2020 ◽  
Author(s):  
Xunwei Deng ◽  
Jingyuan Hou ◽  
Qiaoting Deng ◽  
Zhixiong Zhong
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Direct Sequencing ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Neutropenia ◽  
Severe Toxicity ◽  
Nucleotide Polymorphisms ◽  
Significant Difference ◽  
Grade 3 ◽  
Colorectal Cancer Patients

Abstract Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. The present study was aimed to determine the role of DPYD and GSTP1 variants on patient chemotherapy toxicity risk among the Hakka population, minimize adverse events and in order to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. Results: The data suggest that the incidence of DPYD*5A, DPYD*9A and GSTP1 c.313A>G variants were 37.5%, 24% and 31.7%, respectively. DPYD*2A variant was not found. A total of 38 patients (36.5%) suffered severe neutropenia and 23 patients (22.1%) suffered severe vomiting. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe neutropenia and ulceration (p = 0.010 and p = 0.034, respectively). Patients with GSTP1 c.313A>G wild type contributed to higher risk for grade severe toxicity compared with A/G + G/G genotype (p = 0.024). However, there was no significant difference between patients with DPYD*9A T/T and T/C + C/C genotype for chemotherapeutic toxicity.Conclusions: The results demonstrated that DPYD*5A and GSTP1 polymorphisms were useful predictors for severe events. Screening of single nucleotide polymorphisms of DPYD and GSTP1 in colorectal cancer patients prior to chemotherapy may help to realize personalized therapy.

scholarly journals Potential Impact of DPYD Variation on Fluoropyrimidine Drug Response in sub-Saharan African Populations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jorge E. B. da Rocha ◽  
Zané Lombard ◽  
Michèle Ramsay
Keyword(s):  
Clinical Guidelines ◽  
Dihydropyrimidine Dehydrogenase ◽  
Whole Genome Sequencing Data ◽  
Severe Toxicity ◽  
Sequencing Data ◽  
East African ◽  
Dehydrogenase Enzyme ◽  
African Populations ◽  
Sub Saharan ◽  
Coding Variants

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 (DPYD) gene. There are clinical guidelines to improve safety outcomes of treatment, but these are primarily based on variants assessed in non-African populations. Whole genome sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess variation in DPYD in eight sub-Saharan African populations. Variant functional annotation was performed with a series of bioinformatics tools to assess potential likelihood of deleterious impact. There were 29 DPYD coding variants identified in the datasets assessed, of which 25 are rare, and some of which are known to be deleterious. One African-specific variant (rs115232898-C), is common in sub-Saharan Africans (1–4%) and known to reduce the function of the dihydropyrimidine dehydrogenase enzyme (DPD), having been linked to cases of severe toxicity. This variant, once validated in clinical trials, should be considered for inclusion in clinical guidelines for use in sub-Saharan African populations. The rs2297595-C variant is less well-characterized in terms of effect, but shows significant allele frequency differences between sub-Saharan African populations (0.5–11.5%; p = 1.5 × 10−4), and is more common in East African populations. This study highlights the relevance of African-data informed guidelines for fluorouracil drug safety in sub-Saharan Africans, and the need for region-specific data to ensure that Africans may benefit optimally from a precision medicine approach.

Screening patients for fluoropyrimidine-related toxicity risk.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3529-3529
Author(s):  
Olivier Capitain ◽  
Valérie Seegers ◽  
Jean-Philippe Metges ◽  
Roger Faroux ◽  
Claire Stampfli ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Public Health Problem ◽  
Late Toxicity ◽  
Screening Tests ◽  
Screening Methods ◽  
Severe Toxicity ◽  
Risk Of Death ◽  
The Usa ◽  
Pre Treatment ◽  
Grade 3

3529 Background: Severe, sometimes fatal, toxicity can occur during the 1st or 2nd course of chemotherapy using fluoropyrimidines (FPs), and poses a serious public health problem. FPs carry a 3-5% risk of grade ≥ 3 early toxicities and 0.2% risk of death linked to Dihydropyrimidine Dehydrogenase (DPD) deficiency. Methods: Of 29,000 patients screened since July 2000, 472 were referred to us due to severe toxicity during 1st round 5-FU, or because pre-screening was done too late. Toxicity evaluation was performed according to the NCI scale of adverse reactions to cancer drugs (0=none, 5=death). Patients were previously 5-FU naïve, had different cancers, and received various protocols, eg. 5FU or Capecitabine; bolus±continuous or per os. The reliability of the following 4 pre-treatment screening tests to predict grade≥ 4 toxicity was assessed: 1) DPYD genotype mutation (*2A,*2B,*7, 13, HapB3) 2) Plasma uracil (U) level, 3) Plasma dihydrouracil/uracil ratio (UH2/U) 4) a multiparametric approach with genotyping, UH2/U ratio and key patient factors (age, sex, etc.). McNemar’s test with Bonferroni correction was used for statistical analysis. Results: Of the 472 referred patients, 169 had grade 4 or 5 toxicity, of which 41 died from toxicity. 98 had one or plus DPYD mutation: 42(42.9%)*2A; 43(43.9%)*2B; 3(3%)*7; 4(4%)*13; 8(8.16%) HapB3; 1 was homozygous *2A. Data below compare the 4 screening methods for predicting grade 4-5 toxicity. Conclusions: The multiparametric approach is statistically (p<0.0001) the most efficient in terms of preventing grade 4 and 5 toxicity (death) due to 5-FU treatment. Around 290,000 patients are treated with 5-FU per year in the USA. Assuming a 0.2% mortality rate due to toxicity, around 580 lives could be saved per year using the multiparametric pre-treatment test. [Table: see text]

scholarly journals A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

2020 ◽  
Vol 10 (3) ◽  
pp. 113 ◽  
Author(s):  
Valeria Conti ◽  
Emanuela De Bellis ◽  
Valentina Manzo ◽  
Francesco Sabbatino ◽  
Francesco Iannello ◽  
...  
Keyword(s):  
Systematic Review ◽  
High Performance ◽  
Dosage Reduction ◽  
Dihydropyrimidine Dehydrogenase ◽  
Case Series ◽  
Clinical Monitoring ◽  
Tandem Mass ◽  
Severe Toxicity ◽  
Review Of The Literature ◽  
Dpyd Gene

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

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

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2036
Author(s):  
Paula Soria-Chacartegui ◽  
Gonzalo Villapalos-García ◽  
Luis A. López-Fernández ◽  
Marcos Navares-Gómez ◽  
Gina Mejía-Abril ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Dihydropyrimidine Dehydrogenase ◽  
Case Control ◽  
Regulatory Agencies ◽  
Severe Toxicity ◽  
Predictive Capacity ◽  
Spanish Society ◽  
Dpyd Gene ◽  
Increased Risk ◽  
Control Work

Among cancer patients treated with fluoropyrimidines, 10–40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase (DPYD) 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. Routine genotyping of this gene, which usually includes DPYD *HapB3, *2A, *13 and c.2846A > T (D949V) variants, helps predict approximately 20–30% of toxicity cases. For DPD intermediate (IM) or poor (PM) metabolizers, a dose adjustment or drug switch is warranted to avoid toxicity, respectively. Societies such as the Spanish Society of Pharmacogenetics and Pharmacogenomics (SEFF), the Dutch Pharmacogenetics Working Group (DPWG) or the Clinical Pharmacogenetics Implementation Consortium (CPIC) and regulatory agencies (e.g., the Spanish Medicines Agency, AEMPS) already recommend DPYD routine genotyping. However, the predictive capacity of genotyping is currently still limited. This can be explained by the presence of unknown polymorphisms affecting the function of the enzyme. In this case-control work, 11 cases of severe fluoropyrimidine toxicity in patients who did not carry any of the four variants mentioned above were matched with 22 controls, who did not develop toxicity and did not carry any variant. The DPYD exome was sequenced (Sanger) in search of potentially pathogenic mutations. DPYD rs367619008 (c.187 A > G, p.Lys63Glu), rs200643089 (c.2324 T > G, p.Leu775Trp) and rs76387818 (c.1084G > A, p.Val362Ile) increased the percentage of explained toxicities to 38–48%. Moreover, there was an intronic variant considered potentially pathogenic: rs944174134 (c.322-63G > A). Further studies are needed to confirm its clinical relevance. The remaining variants were considered non-pathogenic.

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2056-2056
Author(s):  
R. Mehra ◽  
L. K. Mattison ◽  
L. Ledbetter ◽  
H. Ezzeldin ◽  
R. B. Diasio ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Memory Loss ◽  
Altered Mental Status ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Dpyd Gene ◽  
Genotypic Analysis ◽  
Grade 3 ◽  
Rate Limiting

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]

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