Dihydropyrimidine Dehydrogenase Deficiency Research Articles

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

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

A fatal case of 5-FU toxicity despite dose adjustment in a patient with a partial DPD deficiency receiving the FLOT regimen

A fatal case of 5-FU toxicity despite dose adjustment in a patient with a partial DPD deficiency receiving the FLOT regimen

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

Several allelic variants of the gene DPYD 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. The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record-based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non-fluoropyrimidine-based regimen was accomplished in 96%. Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.

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

BackgroundDihydropyrimidine 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.MethodsA 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.ResultsA 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.ConclusionsThe 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.

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

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. 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. 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). 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.

Association of plasma uracil concentration with 5-FU pharmacokinetics, dose-limiting toxicity, and DPYD genotype in patients with gastrointestinal cancer.

751 Background: Plasma uracil concentration >16 ng/mL is used in some countries as a screening test for DPD deficiency. We conducted this exploratory study to evaluate the association of uracil concentration with 5-FU exposure, toxicity, and DPYD genotype in patients without known DPD deficiency. The main hypothesis was that lower uracil concentration would be predictive of subtherapeutic 5-FU drug exposure (5-FU AUC < 20 mg*h/L) in patients treated with infusional 5-FU. Methods: The study prospectively enrolled patients with GI cancer who were receiving initial chemotherapy with a regimen containing a 46-hour 5-FU infusion initially dosed at 2400 mg/m2. Study candidates were screened for the DPYD *2A, *13 and c.2846A>T gene variants; variant carriers were excluded. Participants gave pretreatment fasting morning blood samples for determination of plasma uracil concentration and DPYD whole-gene sequencing. Plasma samples were collected at hour 45 of 5-FU infusion in chemotherapy cycles 1 and 2 for determination of 5-FU exposure, measured as the 5-FU AUC. We estimated a linear mixed-effects model to test the association of uracil concentration with 5-FU AUC, adjusting for cycle, sex, creatinine, and 5-FU infusion dose (in mg/m2). Results: There were 29 evaluable participants with a median age of 64 years (range 41-81); nine (31%) were female. The most common cancer sites were colorectal (n = 15) and pancreatic (10). The median (IQR) plasma uracil concentration was 10.4 ng/mL (7.2, 12.6). Data for 5-FU AUC were available for 19 subjects in cycle 1 (median = 22.0 mg*h/L) and 27 subjects in cycle 2 (median = 19.3 mg*h/L). In the mixed-effects model, male sex was significantly associated with 5-FU AUC (beta = -12.0 [95% CI -17.2, -6.7], p <0.001) but plasma uracil concentration was not (beta = 0.35 [-0.16, 0.86], p=0.16). Holding other covariates constant, male sex was associated with a 29% decrease in 5-FU AUC (vs female) and plasma uracil concentration in the lowest quartile was associated with a 12% decrease in 5-FU AUC (vs highest quartile). Three of 29 participants (10%, all male) had uracil concentrations of >16 ng/mL, suggestive of DPD deficiency. The subject with the highest uracil concentration (23.1 ng/mL) had severe toxicity in cycle 1 (neutropenia, mucositis) requiring 5-FU dose reduction; whole gene sequencing identified a rare DPYD missense variant in this subject (c.2185G>A [p.A729T]). The other two subjects with uracil concentration >16 ng/mL did not have culprit DPYD gene variants and tolerated infusional 5-FU at 2400 mg/m2 without early dose-limiting toxicity. Conclusions: Our findings suggest that male sex is more important than low pretreatment plasma uracil concentration as a predictor of risk for subtherapeutic 5-FU drug exposure. This result is consistent with prior evidence that men experience less 5-FU associated toxicity than women.

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Pharmacogenetic Variants Can Influence Optical Medication Use.

Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs. Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization. It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy. Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

Risk of Toxicity From Topical 5-Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles.

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.

Thymidylate Synthase Inhibition with Capped F10 Is Effective in TP53 Null Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is an aggressive cancer of the myeloid linage characterized by progressive marrow failure and death. Responses to therapy are between 50 and 80% but relapse is common and salvage rates once relapsed are low. The risk of relapse is greatly influenced by specific somatic mutations. One of the highest risk mutations in AML involves loss of the tumor suppressor TP53. Patients with AML harboring loss of TP53 function have a dismal prognosis and there is a clear need for new approaches. To identify novel agents with activity against TP53 null AML, a TP53 null and WT isogenic cell line pair was generated using CRISPR/CAS9 in a genetically defined murine AML cell line. Clonal isolates were generated by serial dilution and loss of detectable TP53 was confirmed by Western blotting. A high throughput screen of currently FDA approved agents was performed on these cell lines. When agents were ranked by equal cytotoxicity against TP53 null and WT AML cells 20% (6/30) of the top 30 agents either directly targeted thymidylate synthase or its substrates via inhibition of the folate cycle. This finding suggests that thymidylate synthase (TS) is a key enzyme in TP53 null AML cells. To confirm and extend these results, an additional murine AML TP53 null/WT cell line pair was generated. Chemotherapy resistance was confirmed in the TP53 null cell lines when treated with doxorubicin (Figure 1). Capped F10 (CF10) is a second generation fluoropyrimidine oligonucleotide that is a highly potent inhibitor of TS. In contrast to doxorubicin, CF10 treatment resulted in significant cell death when dosed in the low picomolar range with minimal differences between the null and WT cell lines (Figure 1). To extend this result TP53 null cells were injected into syngeneic recipients and upon engraftment mice were treated with CF10 at 300mg/kg twice weekly or doxorubicin 3mg/kg and cytarabine at 100 mg/kg daily for 5 days. CF10 provided a significant survival benefit in the TP53 null AML in this highly aggressive model where doxorubicin and cytarabine did not (p=0.0057, Figure 2). To confirm a TP53 independent mechanism, competition assays were performed with CAS9 expressing AML cells partially infected with a vector expressing an sgRNA targeting TP53 and containing a GFP reporter. When the mixed population was treated with a titration of doxorubicin there was a highly significant increase in GFP+ cells indicating the involvement of TP53 in doxorubicin mediated cell death. In contrast when cells were treated with a titration of CF10 there was a no significant increase in GFP+ population consistent with CF10 inducing a TP53 independent mechanism of cell death. For CF10 to of use clinically there must be an acceptable therapeutic window. Fluoropyrimidine based therapy can be myelosuppressive especially in patients with low dihydropyrimidine dehydrogenase (DPD) activity. To assess the tolerability of CF10, healthy WAG/RAJ rats were treated with the DPD inhibitor ethynyl uracil at 2mg/kg to mimic DPD deficiency. Animals were then treated with repeated doses of either 141 mg/kg CF10 or the molar equivalent of 50 mg/kg 5-flurouracil (5-FU) and weight determined. In contrast to 5-FU, CF10 treated animals maintained their weight compared to controls (data not shown). Taken together these data suggest that TS is a viable target in TP53 null AML and CF10 is well tolerated and provides a survival benefit in a highly aggressive, chemotherapy resistant model. Ongoing studies will explore the mechanisms involved in CF10 induced cell death.

Implementing a high-reliability, system-wide program for pre-emptive DPD deficiency testing for patients planned for a systemic fluoropyrimidine.

396 Background: Systemic fluoropyrimidine indications span several solid tumor types including gastrointestinal, breast, and head and neck malignancies. Dihydropyrimidine dehydrogenase (DPD) is the primary enzyme involved in fluoropyrimidine metabolism. Pathogenic polymorphisms of the gene encoding DPD (DPYD), occur at a rate of 4-7% and correlate with DPD enzyme deficiency. Failure to detect patients with DPD deficiency, and adjust the dosage preemptively, may result in severe toxicity, including death. Methods: Between December 2022 and May 2023, Dana-Farber Cancer Institute (DFCI) implemented a program across all sites of care to simplify and standardize preemptive DPYD testing for patient planned for a systemic fluoropyrimidine. The opt-out program includes an automated alert recommending DPYD testing when an oncologist orders a new regimen containing either 5FU or capecitabine, education for providers, pharmacists and nurses, patient education materials, standardized tracking of pending results, closed loop notification of providers of abnormal test results, dose adjustment guidelines, and patient tracking. DPYD allelic variants tested: *2A, *7, *8, *10, *13, rs67376798, rs75017182, rs115232898. Results: DPYD testing has increased from a baseline of 14% to 89%. Abnormal DPYD activity (score &lt;2) has been detected in 5.1% of cases (28 of 553). 23 tests were performed preemptively and 5 reactively (all 5 after &gt; grade 3 toxicity events). 27 cases had a single abnormal allele (activity score 1.5 or 1.0); a single case had 2 abnormal alleles (homozygous for rs75017182). Among 11 of the original 23 preemptively tested patients who continued fluoropyrimidine treatment at our facility, standardized dosage reductions were successfully applied for 10 (90.9%). None have experienced &gt; grade 3 toxicity and subsequent dose escalation was possible for 5 (45.5%) patients. Conclusions: We have implemented a voluntary approach to facilitate routine preemptive DPYD testing for patients planned for a systemic fluoropyrimidine achieving an 89% usage rate. 28 of 553 (5.1%) patients were found to have at least a single allelic variant. Preemptive dose reductions were successfully applied for 90.9% of cases. The results provide proof of principle that pharmacogenomic testing can be applied in routine clinical practice and sets the stage for testing additional genes.

S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma

S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma

The Evaluation of Dihydropyrimidine Dehydrogenase Enzyme Level in the Serum of Colorectal Cancer Iraqi Males on Fluoropyrimidine-Based Chemotherapy (Capecitabine).

The cornerstone of systemic chemotherapy for colorectal cancer (CRC) revolves around fluoropyrimidines. This class encompasses 5-fluorouracil (5-FU), which is administered intravenously, along with its oral prodrug counterpart, capecitabine. Central to the metabolism of both 5-FU and capecitabine is the pivotal enzyme dihydropyrimidine dehydrogenase (DPD). Operating at the rate-limiting juncture, DPD assumes a critical role. Notably, a deficiency in DPD significantly elevates the risk quotient for encountering unfavorable outcomes linked to the administration of fluoropyrimidines. This study seeks to assess the significance of DPD enzyme levels in the serum of Iraqi colorectal cancer male patients undergoing fluoropyrimidine-based chemotherapy, specifically with capecitabine. It adopts a case-control design and comprises 80 male participants. Those males are divided into two distinct groups. Group 1 comprises 45 male patients diagnosed with CRC who have experienced relapse subsequent to undergoing chemotherapy based on fluoropyrimidine (capecitabine). Their ages span from 41 to 71 years, and they were treated at the Misan Health Directorate/Misan Center for Tumor Treatment. Group 2 encompasses 35 male patients diagnosed with CRC who underwent fluoropyrimidine-based chemotherapy (capecitabine) without encountering relapse. Their ages range from 40 to 57 years. All participants were provided with comprehensive information regarding the research, and data collection occurred through a structured questionnaire. Subsequent to capecitabine-based treatment, serum samples were collected from CRC patients (stage III). The findings from this research indicate a notable elevation in DPD enzyme activity. Furthermore, a significant reduction in enzyme activity was observed among patients who experienced relapse, in contrast to those who remained non-relapsed.The results indicate that individuals with an insufficiency in DPD are notably more vulnerable to experiencing severe and potentially life-threatening side effects upon exposure to the commonly utilized chemotherapy drug, 5-FU.

DPD deficiency in an Irish oncology centre: Prevalence and clinical implications.

Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019-April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. In those treated 2020-2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25-86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. Other Irish studies estimated prevalence at 11-12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

P-22 Frequency of dihydropyrimidine dehydrogenase (DPD) deficiency detection and adverse events in patients receiving fluoropyrimidine-based therapy in a pancreatic and biliary tract cancer cohort

P-22 Frequency of dihydropyrimidine dehydrogenase (DPD) deficiency detection and adverse events in patients receiving fluoropyrimidine-based therapy in a pancreatic and biliary tract cancer cohort

P-328 Dihydropyrimidine dehydrogenase deficiency frequency and its impact on 5-fluorouracil (5-FU) based chemotherapy toxicity

P-328 Dihydropyrimidine dehydrogenase deficiency frequency and its impact on 5-fluorouracil (5-FU) based chemotherapy toxicity

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

The chemotherapeutic agent 5-fluorouracil (5-FU) is catabolized by dihydropyrimidine dehydrogenase (DPD), the deficiency of which may lead to severe toxicity or death. Since 2019, DPD deficiency testing, based on uracilemia, is mandatory in France and recommended in Europe before initiating fluoropyrimidine-based regimens. However, it has been recently shown that renal impairment may impact uracil concentration and thus DPD phenotyping. The impact of renal function on uracilemia and DPD phenotype was studied on 3039 samples obtained from three French centers. We also explored the influence of dialysis and measured glomerular filtration rate (mGFR) on both parameters. Finally, using patients as their own controls, we assessed as to what extent modifications in renal function impacted uracilemia and DPD phenotyping. We observed that uracilemia and DPD-deficient phenotypes increased concomitantly to the severity of renal impairment based on the estimated GFR, independently and more critically than hepatic function. This observation was confirmed with the mGFR. The risk of being classified 'DPD deficient' based on uracilemia was statistically higher in patients with renal impairment or dialyzed if uracilemia was measured before dialysis but not after. Indeed, the rate of DPD deficiency decreased from 86.4% before dialysis to 13.7% after. Moreover, for patients with transient renal impairment, the rate of DPD deficiency dropped dramatically from 83.3% to 16.7% when patients restored their renal function, especially in patients with an uracilemia close to 16 ng/ml. DPD deficiency testing using uracilemia could be misleading in patients with renal impairment. When possible, uracilemia should be reassessed in case of transient renal impairment. For patients under dialysis, testing of DPD deficiency should be carried out on samples taken after dialysis. Hence, 5-FU therapeutic drug monitoring would be particularly helpful to guide dose adjustments in patients with elevated uracil and renal impairment.

Fluoropyrimidine Dose Based on Uracil Plasma Concentration Impairs Survival in Patients

Fluoropyrimidine drugs (5 flurouracil (5 FU) capecitabine) are the backbone of therapeutic regimens for digestive carcinomas and can lead to severe toxicities. To lower that risk, the French health authorities recommend dose adaptation based on plasma uracil concentration. Since dihydro pyrimidine dehydrogenase (DPD) catabolises more than 80% of 5-FU, a uracil threshold of 16 ng/mL has been considered as partial DPD deficiency.

A Detailed Review on Dihydropyrimidine Dehydrogenase Enzyme Deficiency-Autosomal Recessive Condition

Abstract: Dihydropyrimidine dehydrogenase deficiency (DPD) is an autosomal recessive condition. The DPD enzyme is in charge of the 5-fluorouracil drug’s metabolism. Patients having DPD deficiency, when get administered with 5-fluorouracil drug, leads to drug toxicity due to increased concentration of drug in the body. Determining the DPYD (gene encoding DPD) genotyping and DPYD phenotyping will provide the best strategy to know the DPD deficiency in patients. Tegafur and Capecitabine are available prodrugs for the 5-fluorouracil medication. Genomic techniques appear to be a superior indirect evaluation for screening DPD deficiency in the clinical environment. Other than this there are several diagnostic tests such as Uracil oral loading dose, Uracil Breath test, Rapid UPLC-UV (Ultra performance liquid chromatography-Ultravoilet) method, and DPD activity in mononuclear cells from the peripheral circulation. An antidote Uridine Triacetate is available for treating the toxicity produced by 5-FU (5-Fluorouracil) in DPD deficient patient. Hence, this review explains briefly about the DPD enzyme, its deficiency, its diagnosis, and how to manage the DPD deficient patient undergoing chemotherapy. Keywords: DPD, 5-Fluorouracil, Capecitabine, Tegafur, Uracil Breath test, Uridine triacetate.