ABSTRACTBackgroundThis study evaluated awareness, prevalence, and utilization of dihydropyrimidine dehydrogenase (DPD) testing and pharmacogenomics among oncologists, residents, and clinical pharmacists working in Palestinian hospitals.AimThis study aimed to assess the knowledge and opinions of HCPsspecializing in oncology in Palestine regarding screening for DPYD testing prior to prescribing FP.MethodsA cross‐sectional survey was distributed to 106 HCPs across various hospitals in Palestine.ResultsA notable deficiency in training and implementation of pharmacogenomics was observed, with over 70% of participants lacking formal training in the field. Although there is high awareness of DPD deficiency and its impact, fewer than 50% of participants screen for DPD deficiency prior to prescribing fluoropyrimidines (FP). Standardization and promotion of DPD testing are low, and guidelines for prescribing FP are lacking, leading to variations in clinical practice.ConclusionThese findings highlight the need for enhanced training, standardized protocols, and increased awareness to improve patient safety and outcomes in cancer treatment in Palestine.

10584 Background: Fluoropyrimidines are amongst the most commonly used chemotherapeutic agents in the treatment of gastrointestinal and breast malignancies. Fluoropyrimidines carry a risk of severe adverse events in the 2-3 % of the population with DPD deficiency caused by decreased function variants of DPYD. As a result, pre-treatment testing to identify patients with decreased function variants including DPYD genotyping is critical. However, pre-treatment DPYD genotyping is not yet broadly used in the United States. We hypothesized that our in-house somatic exome DHCancerSeq assay could serve as an effective tool to screen for DPD deficiency. Methods: We identified patients in our health system with somatic whole exome sequencing who had clinical DPYD genotyping using either a limited real time PCR assay (including the *2A, *13, and c.2846A > T alleles) or a dedicated NGS-based PGx panel covering all known clinically relevant mutations in DPYD. HapB3 screening on the somatic whole exome was performed using only the coding sequence variant (c.1236G > A), not the causative deep intronic variant (c.1129-5923C > G), given the known high linkage disequilibrium amongst these variants. We then evaluated concordance of somatic whole exome sequencing and targeted germline genotyping. Results: A total of 115 patients had DPYD genotyping results from both somatic and germline testing and were eligible for evaluation of concordance (48 germline PCR tests and 67 NGS based). There was complete (100%) concordance of genotypes across germline and somatic assays, with genotypes of DPYD *1/*1 (106/106 samples), *1/*2A (3/3), *1/*13 (2/2) and *1/HapB3 (4/4). Conclusions: There was 100% concordance of somatic whole exome sequencing with traditional germline testing for DPYD deficiency. While germline testing remains the standard of care given the nuances of somatic copy number changes, our results suggest that somatic whole exome sequencing is a viable and efficient screening tool for DPD deficiency.

12120 Background: Adverse drug reactions (ADRs) pose a significant challenge to healthcare systems, leading to 6.5-15% of NHS hospital admissions costing over £2.2 billion annually. Genetic factors play a crucial role in predisposing patients to ADRs. One notable example is dihydropyrimidine dehydrogenase (DPD) enzyme deficiency, which affects the metabolism of anticancer drugs like 5-fluorouracil (5FU), capecitabine and tegafur. Current genetic testing in the NHS focuses on four DPYD gene variants associated with European populations, potentially leaving non-European populations at greater risk of drug toxicity. This study aims to expand the genetic evidence base by identifying additional DPYD variants. Methods: This observational study recruited patients who experienced grade 3 or 4 toxicities after receiving 5FU and capecitabine, despite undergoing standard DPYD genetic testing. Participants include both European and non-European patients meeting specified inclusion criteria. Blood samples were collected for genetic testing using either Sanger or next generation sequencing of exons and intron-exon boundaries. Clinical data, including administered dose and toxicity grade, were recorded. Clinicians received genetic results to inform discussions with patients about future treatment. Results: Fifteen patients experienced grade 3-4 toxicity despite standard testing. Of these patients, one patient was heterozygous for c.2846A > T, and therefore predicted to have decreased DPD activity. This patient was wild-type based on NHS standard testing, and was therefore treated with full dose capecitabine, resulting in Grade 3 diarrhoea and vomiting. However, the Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guideline suggests a 50% dose reduction in the presence of this variant. Three patients were found to be heterozygous for other DPYD variants, including c.771C > A, c.2786T > C, c.2766+1G > A, and c.1757T > C. for which there are no current dosing guidelines. The functional impact of these variants requires further study, currently ongoing. All three patients had severe reactions after 1-2 cycles of capecitabine, including one patient requiring a seven-week ICU admission for Grade 4 neutropenic sepsis. Seven patients have found to be heterozygous for DPYD variants that result in normal predicted DPD enzyme activity according to current knowledge, but again further work is needed. Four patients had no DPYD variants. Conclusions: By broadening the genetic analysis of DPD deficiency and identifying new variants, opportunities exist for enhanced patient safety and treatment efficacy. Expanding the variants in DPYD testing in the future, including those found in diverse ancestral populations could lead to improved dosing strategies and reduced the risk of severe ADRs. The findings have the potential to inform future NHS genetic testing protocols and promote equitable healthcare outcomes. Clinical trial information: iras 7086 .

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study.

Abstract Background: Fluoropyrimidine-based (FP) chemotherapy is used to treat solid cancers, including colorectal and breast cancer. The dihydropyrimidinedehydrogenase (DPD) enzyme is in charge of the metabolism of FP; this enzyme is coded by the dihydropyrimidine dehydrogenase (DPYD) gene. Genetic variants inDPYD have been related to an increased risk of severe toxicity. FP toxicity affects about 30-40% of patients, which in some cases may be lethal. DPYD genotyping aims to identify variants that lead to DPD deficiency. The allele frequency of most of theDPYD variants in the Mexican population is currently unknown. Variant identification in the Mexican population can help oncologists in the treatment of patients by reducing the chances of toxicity by adjusting treatment without comprising the antitumoral activity. The aim was to describe the frequency DPYD gene variants associated with FP toxicity in northeastern Mexico's oncologic population. Methods: We analyzed seven DPYD variants by real-time PCR and Sanger sequencing. Two related to reduced activity (c.1129-5923C->G and c.2846A->T)associated with increased risk for toxicity, and four with null activity (c.1156G->T, c.1905+1G->A, c.1679T->G, c.1898delC, and c.299_302delTCAT) with a higher and severe risk for toxicity. Genomic DNA was isolated from 361 subjects: 117 cancer patients and 244 non-cancer subjects. Allele frequency was calculated for each variant and correlated with clinical data. Results: We analyzed a total of 361 subjects, including 117 cancer patients, of which68% had an oncological diagnosis of colorectal cancer, followed by breast cancer with 14%. Metastasic and clinical stage III were present in 42% and 34%, respectively. Grade III (G3) gastrointestinal toxicity was the most common, with a presence of31.9%. The variant c.1129-5923 C>G was found in the heterozygous state in 1.2295%(n=3) of non-cancer patients, the c.2846 A>T variant was found in one non-cancer patient 0.4098% (n=1), and in a 1.7094% (n=2) of cancer patients. The rest of the variants were found in a state of native homozygosity. The two patients carrying the c.2846A>T variant presented a G3 and G4 respectively; one patient required dose adjustment, and the other patient suspended the FP treatment. Conclusions: The allele frequency for two of the seven analyzed variants (c.1129-5923C>G, and c.2846A>T) was higher than reported for the global population (0.00476and 0.005166). DPYD genotyping may help to identify people who are at higher risk of developing severe FP toxicity. Personalized medicine allows oncologists to modify the treatment before it begins. Citation Format: María L. Garza-Rodríguez, Francisco J. Villarreal-Alvarado, Axa N. Vega-García, Valeria J. Gómez-Ordaz, Irasema Martínez-Ramos, Vanessa N. Ortiz-Murillo, Azalea E. Urdiales-Ordoñez, Alan Burguete-Torres, Fernando Alcorta-Nuñez, Carlos H. Burciaga-Flores, Moisés González-Escamilla, Oscar Vidal-Gutiérrez, Diana C. Pérez-Ibave. Allele frequency of DPYD genetic variants for fluoropyrimidines metabolism in a Northeast Mexican population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6829.

Fluoropyrimidines (FPs) are antineoplastic agents used for the treatment of various solid tumors, especially gastrointestinal cancers. Patients with variations in dihydropyrimidine dehydrogenase gene (DPYD), which can determine the partial or complete deficiency of the dihydropyrimidine dehydrogenase enzyme (DPD), are at an increased risk of developing severe and potentially life-threatening toxicity. Worldwide the introduction of pharmacogenetic testing into clinical practice has been a slow process and in our center the analysis of the DPYD gene has been adopted since April 2020. We evaluated the clinical application of routine DPYD screening and its ability to prevent early-onset of fluoropyrimidine-related toxicity in patients treated at the Oncology Reference Center of Basilicata (IRCCS-CROB), a recognized cancer centre in Southern Italy. From April 2020 to November 2022, 300 patients (male 137; female 163) diagnosed with various types of cancer were subjected to DPYD genotyping, before starting treatment with FPs. In accordance with the current European Medicines Agency (EMA) and the Italian Association of Medical Oncology (AIOM) guidelines patients were tested for four DPYD variants that are associated with reduced DPD activity. FPs dose adjustments in DPYD variant carriers were made following the previously mentioned guidelines. Three hundred patients underwent DPYD testing and thirteen (4.3%) patients were found to be heterozygous variant carriers; ten out of thirteen patients received FP dose reduction as indicated by the guidelines, one out of thirteen patients received alternative treatment, two of the thirteen patients received no treatment at all. The main toxicities observed in patients who received a DPYD genotype-based dose reduction were anemia, neutropenia, nausea and mucositis but events were primarily grade 1 or 2. Our experience confirms the technical feasibility and the usefulness of DPYD genotyping to reduce the risk of severe FPs toxicities.

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113 Background: Gastrointestinal cancers are among the most prevalent malignancies, often treated with chemotherapeutic agents whose efficacy and toxicity can be influenced by genetic variations. Pharmacogenetic testing for key metabolic genes, including DPYD, UGT1A1, and G6PD, can guide personalized treatment approaches. Methods: We analyzed samples from 3,519 individuals for genotyping using semiconductor-based Next-Generation Sequencing (NGS) technology. High-quality genomic DNA was extracted and subjected to target enrichment via high multiplex PCR amplification using an NGS panel targeting variants of key metabolic genes, including DPYD, G6PD, and UGT1A1. Results: For the DPYD gene, 96% of patients were normal metabolizers. However, 4% intermediate and 0.17% individuals had poor metabolizer status. Poor metabolizers possess homozygous non-functional alleles, leading to complete dihydropyrimidine dehydrogenase (DPD) deficiency and increased toxicity risk with fluoropyrimidine drugs like 5-fluorouracil (5-FU), Capecitabine, and Tegafur. Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil. 5-FU is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Intermediate metabolizers exhibit approximately 50% reduced DPD activity, necessitating a 50% reduction in starting doses followed by careful titration based on toxicity. UGT1A1 analysis revealed 46% normal, 42% intermediate, and 12% poor metabolizers, affecting Irinotecan metabolism and toxicity risks. Poor metabolizers show decreased UGT1A1 activity, resulting in reduced clearance of Irinotecan and increased risk of dose-limiting toxicities. These patients are also at higher risk for neutropenia, diarrhea, and asthenia, requiring starting dose adjustments. Additionally, they may experience elevated hyperbilirubinemia with treatments like Regorafenib. Recognizing G6PD deficiency in GI cancers can prevent serious complications and ensure safer treatment options. G6PD testing indicated that 98% were homozygous wildtype, 2% heterozygous, and 0.31% homozygous/hemizygous deficient. Patients with homozygous/hemizygous deficient genotype may be at increased risk for drug-induced hemolysis, particularly when treated with Dabrafenib. Conclusions: These findings highlight the therapeutic significance of incorporating genetic testing into clinical practice to tailor treatments, enhance drug efficacy, and minimize side effects in GI cancer management. By integrating pharmacogenetic insights, the safety and effectiveness of therapies can be significantly improved, ultimately leading to better patient care in GI oncology.

226 Background: 5-Fluorouracil (5-FU), a common chemotherapy for solid tumors, is metabolized primarily by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. With > 200 known variants, individuals with nonfunctional DPYD alleles exhibit impaired 5-FU metabolism and are at risk of severe toxicity. Approximately 35% of the population has partial DPD deficiency, and 0.2% completely lack enzymatic activity. Despite this, DPYD genotyping is not standard practice. This study evaluates the use of non-invasive saliva samples for DPYD genotyping and combines AI-based molecular prediction modeling to search for novel variants within DPYD coding region. Saliva samples were collected from fifty-six healthy individuals and from gastrointestinal (GI) cancer patients including a family cohort of nineteen individuals and three unrelated patients undergoing chemotherapy. Methods: gDNA was sequenced for nine DPYD variants reported to reduced or abrogate DPD activity: c.1905+1G > A, c.1679T > G, c.2846A > T, c.1129-5923C > G, c.1236G > A, c.299_302delTCAT, c.703C > T, c.2983G > T, and c.557A > G. cBioPortal was utilized to search the TCGA database for studies involving colon cancer patients with novel DPYD mutations exhibiting a total FIS score of at least 2 or identified through 3D modeling of DPD using PyMol based on their proximity to or the presence of polar contacts within the active site. Putative pathogenic mutations were analyzed using AlphaMissense and ChimeraX to assign a RSMD score, assessing their potential negative impact on DPD function. Results: Computational studies identified three mutations in DPYD from TCGA colon cancer patients with an unknown impact on DPD and a FIS greater than 4 (c.198G > C/T, c.2161G > A, c.2185G > A), suggesting potential disruption of its function. Four mutations (c.424T > G, c.427T > G, c.2460G > C, c.2909C > A) were identified through protein modeling using PyMol, but only two had a FIS greater than 2. Of these seven identified mutations, four (c.198G > C/T, c.2161G > A, c.2185G > A, c.2909C > A) also scored highly using AlphaMissense and ChimeraX. In silico prediction models from VarSome listed c.2185G > A as Pathogenic Moderate and c.2909C > A as Pathogenic Very Strong. Sequencing of saliva samples indicated mutations c.1129-5923C > G and c.1236G > A were present in four and three volunteers, respectively, and c.1905+1G > A in one case. Mutations identified in GI cancer patients were c.1129-5923C > G and c.1236G > A. Conclusions: By combining computational modeling with the analysis of naturally occurring mutations in colon cancer patients, we have successfully identified potentially pathogenic mutations in the DPYD gene. This information can enhance existing clinical diagnostic tests, providing a more comprehensive assessment of DPYD mutations, including novel variants.

The safety of systemic fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) is impacted by germline genetic variants in DPYD, which encodes the dihydropyrimidine dehydrogenase (DPD) enzyme that functions as the rate-limiting step in the catabolism of this drug class. Genetic testing to identify those with DPD deficiency can help mitigate the risk of severe and life-threatening fluoropyrimidine-induced toxicities. Globally, the integration of DPYD genetic testing into patient care has varied greatly, ranging from being required as the standard of care in some countries to limited clinical use in others. Thus, implementation strategies have evolved differently across health systems and countries. The primary objective of this tutorial is to provide practical considerations and best practice recommendations for the implementation of DPYD-guided systemic fluoropyrimidine dosing. We adapted the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to cover topics including the clinical evidence supporting DPYD genotyping to guide fluoropyrimidine therapy, regulatory guidance for DPYD genotyping, key stakeholder engagement, logistics for DPYD genotyping, development of point-of-care clinical decision support tools, and considerations for the creation of sustainable and scalable DPYD genotype-integrated workflows. This guide also describes approaches to counseling patients about DPYD testing and result disclosure, along with examples of patient and provider educational resources. Together, DPYD testing and clinical practice integration aim to promote safe prescribing of fluoropyrimidine therapy and decrease the risk of severe and life-threatening fluoropyrimidine toxicities.

While standard doses of adjuvant fluoropyrimidine-based chemotherapies are generally safe for most patients, the risk of severe adverse drug reactions (ADRs) is increased for those with dihydropyrimidine dehydrogenase deficiency (DPYD), a genetic variation that affects drug metabolism. The objective of this study was to examine the cost effectiveness of offering DPYD pharmacogenetic-guided care, where genetic testing informs personalized dosing versus the current standard of care (SoC), which involves administering fluoropyrimidine-based therapies without prior genetic screening, for local or metastatic breast cancer patients in Qatar. We developed a two-stage decision analysis, with an analytic tree model over a 6-month period, followed by a life-table Markov model over a lifetime horizon. We compared the current SoC with the alternate strategy of DPYD genetic screening in patients living in Qatar with local or metastatic breast cancer who were eligible for adjuvant fluoropyrimidine therapy. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were estimated from Hamad Medical Corporation, Qatar. The short-term outcome included the incremental cost-effectiveness ratio (ICER), defined as cost per success (survival without grade III/IV ADRs) at 6 months. The long-term outcome was the ICER, defined as cost per quality-adjusted life year (QALY) gained, with a 3% annual discount rate. The study adopted a public healthcare perspective in Qatar. Sensitivity analyses were conducted to explore the impact of key input parameters on the robustness of the model. In the short-term model, at its base case, DPYD genomic screening was dominant over SoC with a mean cost-saving of QAR84,585 (95% confidence interval [CI], 45,270-151,657). This cost saving reflects the overall economic benefits associated with the implementation of DPYD genomic screening. In the long-term model, compared to the current SoC, DPYD genetic screening would result in an ICER of QAR21,107 (95% CI -59,382-145,664) per QALY gained. Based on our model, implementing DPYD genetic screening to detect DPYD mutations in breast cancer patients before therapy initiation seems to be a cost-saving and cost-effective strategy in Qatar.

Introduction: Cancers are ranked among diseases with increasing prevalence and which treatment is based on cytotoxic products. The elimination of these products can be stopped by the deficiency of an enzyme which plays an important role in metabolism (DPD). This phenomenon can be the trigger of side effects. It is within this context that we decided to assay parameters (uracil, dihydrouracil) that allow us to evaluate the activity of DPD. Methods: The study was carried out in patients with cancer. All clinical signs after chemotherapy were recorded. A blood sample was taken from these patients on EFTA tube and centrifuged at 4000 revolutions per minute for 8 minutes. Uracil (U) and Dihydrouracil (UH2) parameters were determined using the HPLC method after extraction. Results: In our study population, we identified 29 patients who had not yet started chemotherapy whereas 74 had already started. Of those who started chemotherapy, 92% had side effects and only 8% were found without symptoms. In patients with U < 16 ng/ml, 45 had side effects while 20 did not. Patients with UH2/U >13; 25 had adverse effects while 12 did not. Regarding DPD status among patients without DPD deficiency, 22 had adverse effects (21.4%) and 12 did not (11.7%). Conclusion: The association between uracil concentrations and side effects showed that uracil levels above 150 ng/ml were consistently related to serious side effects, such as vomiting, diarrhea and general fatigue.

Rapid Biomonitoring of Fluoropyrimidine-based Chemotherapy Drugs and their Biometabolites in Colorectal Cancer Patients’ Blood Samples using an In-syringe-based Fast Drug Extraction Technique followed by LC-MS/MS Analysis

Introduction: Acute ischemia of the bowel is associated with mortality rates of up to 80%. While early detection is key to appropriate management, the utility of investigative modalities is limited by poor sensitivity and specificity. Objectives: This report outlines the case of a patient with investigation results unremarkable for underlying ischemia, where clinical suspicion alone led to its diagnosis. Case Report: A 37-year-old female presented to a tertiary hospital ED with severe, generalized, abdominal pain for several hours after eating at a restaurant. She had a known history of treatment for breast cancer, as well as dihydropyrimidine dehydrogenase (DPD) deficiency. On examination, the patient was tachycardic and she had vague tenderness was in the right upper and left lower quadrants. A venous blood gas demonstrated normal lactate. Initial CT abdomen and pelvis with intravenous (IV) contrast showed minimal bowel edema only. Pain persisted despite high-dose opioids, and was out of proportion to physical examination. Despite a second CT angiogram revealing no vascular occlusion or ischemia, persistent pain prompted a diagnostic laparotomy, uncovering an infarcted duodenal segment, necessitating resection and anastomosis. Post-op, the patient recovered well and was discharged without complications. Discussion: This case highlights the importance of clinical suspicion in diagnosing bowel ischemia. Typical risk factors such as advanced age, atrial fibrillation, coagulopathy, cardiac disease, or a low-flow state were not present in this patient. Abdominal pain is present in around 95% of patients with mesenteric ischemia. Despite a myriad of proposed lab markers and diagnostic modalities, very few have shown to be reliable at identifying mesenteric ischemia. Diagnosis of mesenteric ischemia relies on a high index of suspicion in a patient with abdominal pain, especially one that is out of proportion and possibly associated with postprandial worsening. Conclusion: In the acute care of patients with potentially life-threatening conditions, especially bowel ischemia, care must be taken into account for the most important cause for severe pain. If conventional markers for disease do not show typical abnormalities, it does not always exclude the diagnosis. Clinical gestalt for an unwell patient takes precedent and should always guide disposition decisions.

PurposeInherited dihydropyrimidine dehydrogenase (DPD) deficiency is a risk factor for severe 5-fluorouracil toxicity. We report a phenotyping approach (thymine challenge test) to prospectively determine DPD activity and the association with severe adverse events.MethodsThe primary aim of this prospective study was to determine whether a thymine challenge test could prospectively identify patients at risk of severe toxicity from treatment with 5-fluorouracil/capecitabine in combination chemotherapy schedules or monotherapy. The focus was prediction of those at risk of ≥ grade 3 gastrointestinal toxicity. DPD activity was determined from the thymine/dihydrothymine (THY/DHT) ratio measured in a urine sample after a thymine test dose (250 mg, oral).ResultsOf the 166 patients, 11.7% had severe diarrhoea/mucositis. The THY/DHT ratio was not significantly different in these individuals compared to those with minimal toxicity. However, post hoc analysis found decreased DPD activity in those who had non-gastrointestinal toxicity, most notably grade ≥ 2 Hand-Foot syndrome (p = 0.001).ConclusionThe data do not support our primary hypothesis that this phenotyping approach would discriminate those at risk of severe/life-threatening gastrointestinal toxicity. The clinical factors which influence gastrointestinal toxicity, particularly in patients receiving CAPOX require further investigation.Clinical trial registrationACTRN 12,617,001,109,392 registered 28/07/2017.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00280-025-04804-6.

The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance. This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database. We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values. Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.

Reply to: "Give Patients the Choice to Test for DPD Deficiency Before Fluoropyrimidine Chemotherapy," "Large-Scale DPD Testing Should Be More Than an Option," and "A Big Problem With a Feasible Solution, Not a Small Problem With a Complex Solution".

EE401 Budgetary Impact of Pre-Therapeutic DPD Deficiency Screening in Fluoropyrimidine-Treated Cancer Patients in Algeria

Background/Objectives:MIR27A rs895819 polymorphism has emerged as a potential additional pharmacogenomic marker of fluoropyrimidine response. Current evidence on its potential effect on miR-27a expression, which represses DPD activity, leading to DPD deficiency and increased fluoropyrimidine-associated toxicity risk, is scarce and inconsistent. We have analyzed the effect of MIR27A rs895819 polymorphism on miR-27a-3p plasma expression levels under different models of inheritance to contribute further evidence on its plausible biological role in miR-27a expression. Methods: A total of 59 individuals with no medical history of cancer were included in this study. MIR27A rs895819 genotyping and miR-27a-3p expression were analyzed by using predesigned TaqMan assays. Results: The frequency of TT, TC, and CC genotypes was present at a prevalence of 50.8%, 44.1%, and 5.1%, respectively. Individuals carrying the CC genotype presented with decreased miR-27a-3p expression (0.422 fold-change versus TT, p = 0.041; 0.461 fold-change versus TC, p = 0.064), whereas no differences were present between TT and TC individuals (1.092 fold-change, p = 0.718). miR-27a-3p expression was decreased in CC individuals under a recessive model of inheritance (0.440 fold-change, p = 0.047). No differences were found in dominant (TT vs. TC+CC, 0.845 fold-change, p = 0.471) or over dominant (TT+CC vs. TC, 0.990 fold-change, p = 0.996) models of inheritance. Conclusions:MIR27A rs895819CC genotype leads to severely reduced miR-27a-3p expression in plasma. Further study of this association is warranted in cancer patients to apply MIR27A genotyping in therapeutics to identify fluoropyrimidine-treated patients who are at a decreased risk of experiencing fluoropyrimidine-induced severe toxicity.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.