Introduction5-Fluorouracil (5-FU) is a chemotherapeutic agent used in various malignancies. 5-FU-induced leukoencephalopathy is a rare but reversible neurotoxic effect occurring within days of administration. Symptoms include confusion, agitation, and cognitive disturbances, with severe cases potentially causing coma. Diagnosis is supported by magnetic resonance imaging (MRI) showing characteristic brain changes. Treatment involves discontinuing 5-FU and initiating supportive care. Most patients recover within one week, but relapse may occur with repeated exposure, making early recognition critical.Case reportA 42-year-old male with recurrent Stage IV gastric adenocarcinoma and chronic kidney disease developed progressive 5-FU-related leukoencephalopathy after repeated exposure. MRI findings and symptoms of confusion, disorientation, and memory deficits were consistent with 5-FU leukoencephalopathy. Initial work-up was inconclusive, therefore, treatment was continued. Neurologic symptoms worsened after further cycles, leading to chemotherapy discontinuation and surgical resection. Disease recurrence led to reinitiation of modified 5-FU therapy, triggering acute neurotoxicity confirmed by MRI.Management and outcomeThe patient was managed by discontinuing 5-FU, beginning high-dose intravenous thiamine and methylprednisolone, and providing supportive care. Neurologic symptoms including confusion, facial diplegia, and unsteady gait gradually resolved. By Day 9, he returned to baseline mental status without deficits.DiscussionEarly recognition and intervention in 5-FU-induced leukoencephalopathy is crucial, especially in patients with renal dysfunction or repeated exposures. Dihydropyrimidine dehydrogenase (DPD) deficiency has not been directly implicated in this condition. Metabolic disruption and thiamine depletion contribute to pathogenesis. Prompt 5-FU discontinuation and initiation of supportive care can hasten recovery. Clinical vigilance is imperative in patients with known risk factors.

112 Background: Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity, especially in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Four DPYD polymorphisms ( DPYD *2A, *13, p.Asp949Val, HapB3) are validated to increase FP toxicity risk but the association for many other DPYD variants has not been demonstrated. This study aims to identify additional DPYD polymorphisms that increase FP-related toxicity. Methods: This retrospective study used genetic data from the Michigan Genomics Initiative institutional biobank, which is linked to the University of Michigan Rogel Cancer Center electronic medical record. Adults treated with standard doses of systemic FP (5-fluorouracil or capecitabine) for any tumor type with available genetic data were included. The primary toxicity endpoint was a composite of CTCAE grade ≥3 toxicity or treatment modification due to toxicity in the first two FP cycles. A literature-curated list of suspected deleterious DPYD variants beyond the four validated variants was classified as uncommon (minor allele frequency <0.01) or common. Uncommon variants were analyzed in aggregate whereas common variants were analyzed individually, excluding patients carrying validated variants. The genetic association with toxicity was analyzed via logistic regression adjusted for demographic and treatment factors. Toxicity prediction was estimated using positive (PPV) and negative (NPV) predictive values for testing the validated variants with and without the uncommon variants. Results: Among 849 eligible patients, the composite toxicity endpoint occurred in 25.1% (16.5% grade ≥3 toxicity, 23.2% treatment modification). Genetic data were available for four uncommon and six common suspected deleterious DPYD variants. In the primary analysis of 799 patients who did not carry a validated variant, carriers of an uncommon variant (1.1% of patients; Table 1) had significantly higher risk of toxicity than non-carriers (66.7% vs. 23.7%; adjusted OR 7.36; 95% CI 1.75–38.2; p=0.009). None of the common variants were associated with toxicity (data not shown). Toxicity prediction in the entire cohort (n=849) was slightly improved by testing the uncommon and validated variants vs. testing only the validated variants (PPV= 44.1% vs. 40.0%, NPV=76.3% vs. 75.8%). Conclusions: Four uncommon DPYD variants that, in combination, increase FP toxicity risk and improve toxicity risk prediction were identified. Inclusion of these variants in DPYD testing would identify more patients with high toxicity risk who should receive adjusted FP doses to prevent severe toxicity. Incidence of toxicity among carriers of each uncommon variant. Uncommon variant Incidence of toxicity among carriers c.1757T>C, p.Val586Ala, rs374527058 0% (0/1) c.557A>G, p.Tyr186Cys, rs115232898 67% (4/6) c.274C>G, p.Pro92Ala, rs143986398 100% (1/1) c.187A>G, p.Lys63Glu, rs367619008 100% (1/1)

TPS250 Background: Fluoropyrimidine (FP) is a common chemotherapy class used across multiple tumor streams, including first line colorectal cancer management. Approximately 30% of patients develop serious toxicities with standard doses, potentially requiring hospitalization, intensive care admission and occasionally death. FP chemotherapy is primarily metabolized by dihydropyrimidine dehydrogenase (DPD, encoded by DPYD ), with DPD deficiency accounting for a significant number of serious toxicities. DPYD genotyping is a valid method of indirect measurement of DPD activity and has been implemented into routine care in some regions, enabling genotype-guided dosing. Despite mounting evidence, uptake of DPYD testing in Australia is currently sporadic and typically self-funded by the patient. This study will be the first to provide nation-wide prospective data on the feasibility and effectiveness of DPYD genotyping to direct FP dosing within the Australian health care system. Methods: This is a prospective, single arm, non-randomized study, aiming to recruit 5000 adult patients across Australia with solid organ malignancies intended to receive FP-based chemotherapy for the first time (trial registered 12/13/2023, Australian and New Zealand Cancer Trials Registry ACTRN12623001301651). DPYD genotyping will be performed for the key variants; c.1905+1G>A, ( DPYD *2A, rs3918290), c.2846A>T (rs67376798), c.1679T>G (DPYD*13, rs55886062.1) and c.1236G>A (rs56038477), with dose adjustments performed in accordance with published Australian guidelines. The primary outcome is incidence of serious (CTCAE v5.0 Grade 3+) FP-associated toxicities in the first 60 days in heterozygote DPYD variant carriers who receive a genotype-guided dose-adjustment, compared to: i) current standard of care (as assessed by a retrospective review of 500 consecutive cases); ii) contemporaneous cases without these variants treated with standard doses; and iii) variant carriers in this study that do not receive genotype-guided dosing. Primary endpoint data is anticipated to be completed by Q4 2027. Secondary outcomes include DPYD variant frequency, health economic and cost effectiveness analysis, and impact of dose adjustment on cancer outcomes. To date, 27 sites have been activated, with over 1200 participants enrolled. Completion of this study will inform a standardised approach for DPYD genotyping to minimise FP complications in Australia. Clinical trial information: ACTRN12623001301651 .

Introduction: Deficiency of the dihydropyrimidine dehydrogenase enzyme can result in capecitabine-related toxicity due to genetic alterations in the DPYD gene, leading to complete or partial DPD deficiency and poor or intermediate metabolizer phenotypes. The distribution of DPYD variants varies across populations. While routine DPYD genotyping is recommended in Western populations, data from India, particularly from next-generation sequencing (NGS)-based studies, remain limited. Methods: This exploratory analysis was conducted within the D-TORCH trial, a randomized, double-blind, placebo-controlled study evaluating topical diclofenac for prevention of capecitabine-induced hand-foot syndrome. Germline whole-exome sequencing was performed in consenting patients prior to capecitabine initiation. DPYD variants were identified using an NGS pipeline, annotated via ANNOVAR and PharmGKB, and classified according to CPIC guidelines. Results: Seventy-six patients underwent DPYD sequencing; 54 (71%) carried at least one variant and 22 (29%) were wild-type. Thirteen coding or splice-site variants were identified, including three (3.9%) associated with an intermediate metabolizer phenotype; no poor metabolizers were detected. The most common variants were classified as normal metabolizers. Grade 2 toxicity occurred in 63.6% of variant carriers and 55.6% of wild-type patients, with diarrhea and mucositis being most frequent. No significant association was observed between DPYD variant status and toxicity. Discussion: This first NGS-based DPYD report from India highlights the low prevalence of clinically actionable variants. Larger studies are required to validate these findings and guide population-specific fluoropyrimidine dosing strategies.

Screening for dihydropyrimidine dehydrogenase (DPD) deficiency has been recommended by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) to prevent fluoropyrimidine toxicity. Depending on national guidelines, it relies on phenotyping or variants genotyping. We assessed the benefit of DPYD sequencing to identify unreported variants that may alter enzyme function. We retrospectively analyzed DPYD next-generation sequencing results obtained from 1145 individuals at Limoges University Hospital between November 2020 and July 2025. Fifty-one DPYD variants were identified including several rare variants and copy-number variation (CNV) that are not addressed in current guidelines. Four were common (MAF ≥ 5%), 6 rare (MAF ≥ 0.5% and < 5%) and 41 very rare (MAF < 0.5%). Eight showed a Clinical Pharmacogenetics Implementation Consortium (CPIC) score indicative of decreased or null activity; 12 were classified normal-function allele, and 31had no CPIC annotation. In this cohort, 73 (6.3%) individuals carried at least one decreased-function allele, while 28 (2.4%) had potentially damaging rare or structural variants (including 5 CNVs). NGS analysis enables the identification of DPYD rare or structural variants with potential functional impact, thereby improving the genetic assessment of DPD deficiency.

Clinical implementation and outcome evaluation of dihydropyrimidine dehydrogenase (DPYD) pharmacogenomic testing for fluoropyrimidine dosing in a Canadian Provincial Healthcare center.

1173eP Frequency of dihydropyrimidine dehydrogenase (DPD) deficiency in patients receiving fluoropyrimidine-based chemotherapy for solid tumors: A single-centre experience in Dubai, UAE

Dihydropyrimidine dehydrogenase (DPD) deficiency, an autosomal recessive metabolic disorder, causes a considerable deficit in the patient's metabolism of fluoropyrimidine drugs, most notably 5-fluorouracil (5-FU) and capecitabine. There is a higher frequency of severe toxicities after a fluoropyrimidine regimen among patients with GI and hepatopancreaticobiliary (HPB) malignancies on chemotherapy because of this metabolic deficiency. This prospective study aims to assess the rate of DPD deficiency and clinical significance of DPD deficiency in patients receiving fluoropyrimidine chemotherapy at a tertiary oncology center in India. From March 2024 to February 2025, we prospectively recruited 146 patients with histologic confirmation of GI and HPB cancers who were commencing a 5-FU- or capecitabine-based regimen. We performed pretreatment DPD tests on all patients using TRUPCR DPYD reverse transcriptase polymerase chain reaction for four known variants. Severe toxicities (Common Terminology Criteria for Adverse Events v5.0) were assessed after the first cycle of chemotherapy. Dose reductions, advances in therapy, and admissions were also noted. Of the 146 study participants, 11 (7.5%) had a DPYD mutation. HapB3 (rs56038477) was the most commonly encountered variant (72.7% of patients), along with registries of DPYD*2A (18.2%) mutation and mutation c.2846A>T (9.1%). Severe toxicities (grade ≥3) were above other grade toxicities (61.6%) in mutation carriers (72.7%) as compared with mutation noncarriers (37.0%, P = .03). Neutropenia, diarrhea, and thrombocytopenia were the common toxicities at a frequency of 18.5%, 12.3%, and 15.1%, respectively. After dose reduction, 90.9% of mutation carriers required a dose reduction versus 14.8% of mutation noncarriers (P < .001). Both groups had no problems in completing treatment. Individuals with DPYD mutations experience increased toxicity and dose adjustments; however, treatment efficacy was not affected. This indicates that a coordinated effort that incorporates routine DPYD testing can mitigate treatment toxicities and individualized fluoropyrimidine dosing for patients with GI and HPB cancers.

Introduction We present a unique case of capecitabine and oxaliplatin (CAPOX) therapy presenting as dysarthria as an uncommon side effect in the context of a TIA and review relevant literature to highlight potential mechanisms and clinical implications. Case Presentation A 65‐year‐old male with colon adenocarcinoma (pT2N1aMX) on capecitabine (1000 mg/m 2 BID, 2 weeks on/1 week off) and oxaliplatin (130 mg/m 2 every 3 weeks) presented with a transient episode of acute dysarthria around 16:40, shortly after receiving chemotherapy earlier that day. His history included a remote left occipital hemorrhagic infarct (likely from paroxysmal atrial fibrillation), chronic left lower extremity DVT on apixaban 5 mg BID, hypertension, hyperlipidemia, and DM. His wife noted sudden slurred, unintelligible speech while he was preparing lunch; symptoms resolved within 15 minutes. He was asymptomatic upon ED arrival. Stroke workup, including brain MRI and MRA, was unremarkable. Given his vascular risk factors, cancer‐associated hypercoagulability, and temporal proximity to chemotherapy, a diagnosis of CAPOX‐induced transient ischemic attack was made. He was discharged on apixaban, and both he and his oncologist—who opted to continue the current regimen‐were counseled on the diagnosis. Discussion Chemotherapy‐induced neurotoxicity poses a frequent clinical challenge. Oxaliplatin is commonly associated with sensory peripheral neuropathy and pharyngolaryngeal dysesthesia, with occasional reports of headache, body pain, cranial nerve palsy, dysarthria, dysphagia, and rarely, posterior reversible encephalopathy syndrome (PRES). Capecitabine‐induced neurotoxicity occurs in ∼0.5% of cases, typically presenting as cerebellar syndrome with ataxia, dysarthria, and nystagmus, and more rarely, seizures or acute leukoencephalopathy. The underlying mechanisms remain unclear but may involve ammonia accumulation, capecitabine‐induced thiamine deficiency, or dihydropyrimidine dehydrogenase (DPD) deficiency, an enzyme essential for capecitabine metabolism. Animal studies suggest CAPOX may disrupt the blood‐brain barrier and increase extracellular ATP levels, potentially contributing to CNS toxicity. Dysarthria as an isolated chemotherapy‐related symptom is rare and may mimic acute cerebrovascular events, risking misdiagnosis. Early recognition is critical to avoid unnecessary treatment delays or dose modifications. Though typically self‐limiting, symptom severity varies. Slower infusion rates may help mitigate recurrence, and decisions on continuing chemotherapy should be guided by a careful risk‐benefit discussion with the patient. Conclusion Clinicians, pharmacists, and patients should be aware of the rare but significant neurotoxic effects of oxaliplatin and capecitabine. Nonetheless, a thorough evaluation for stroke remains essential, given the elevated risk from malignancy‐associated hypercoagulability. image

Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, is a key enzyme in pyrimidine catabolism, and its deficiency leads to severe toxicity in patients treated with 5-fluorouracil (5-FU). While pathogenic DPYD variants account for many cases of DPD deficiency, they do not fully explain all instances of 5-FU sensitivity, suggesting additional genetic factors are involved. Recent studies have implicated variants in CIAO1, a gene encoding a subunit of the cytosolic iron-sulfur (Fe-S) cluster assembly targeting complex, in reducing DPD stability and function. In this study, we established a C. elegans model to assess DPD deficiency and 5-FU sensitivity. Using a dpyd-1 knockout and CRISPR-generated ciao-1 variants that mirror patient-derived variants (p.Trp184Cys, p.His193Tyr, and p.Arg65Trp), we provide the first in vivo evidence that pathogenic variants in CIA complex components can lead to DPD deficiency and, consequently, heightened 5-FU toxicity. Our findings highlight the critical role of CIAO1 in DPD function and 5-FU tolerance, expanding the genetic landscape of DPD deficiency and offering a robust platform for functional evaluation of pathogenic variants.

5-Fluorouracil (5-FU) and its prodrug, capecitabine, are widely used in chemotherapy for various cancers, including colorectal, breast, and gastrointestinal malignancies. While their common toxicities are well documented, uncommon, and severe side effects, such as cardiotoxicity, neurotoxicity, and hyperammonemia-related encephalopathy, remain poorly understood, particularly in certain populations. This study aimed to investigate the prevalence and severity of these rare adverse effects in patients with cancer in Saudi Arabia. This cross-sectional observational study was conducted at King Saud University Medical City over a 2-year period and enrolled 272 patients who received 5-FU or capecitabine. Collected data included demographics, cancer type, treatment regimen, and reported adverse effects. Statistical analyses assessed the frequency, severity, and risk factors associated with uncommon toxicities. A total of 39.7% of patients experienced side effects, with neurological symptoms (39.6%) being the most common, followed by ocular (12.6%) and cardiac (11.8%) toxicities. Most adverse effects occurred during the initial chemotherapy cycles. Factors such as sex, body mass index, and cancer stage influenced toxicity risk, with capecitabine showing a stronger association with side effects than 5-FU. These findings emphasize the need for population-specific studies to improve early detection and management of rare toxicities related to 5-FU and capecitabine. Understanding the genetic and environmental contributors to adverse reactions could enhance treatment safety and efficacy in Saudi patients with cancer. Although dihydropyrimidine dehydrogenase deficiency is a recognized risk factor for severe 5-FU toxicity, routine dihydropyrimidine dehydrogenase genetic testing was not conducted in this cohort. This limitation underscores the need for further research in this area, particularly among Saudi patients.

Abstract Background 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used chemotherapy drugs for treating various solid tumours, including colorectal, breast, and gastrointestinal cancers). Annually, around two million patients receive treatment with these drugs. However, a significant challenge with 5-FU treatment is toxicity. Between 10-30% of patients experience severe side effects, and in about 0.5-1% of cases, these toxicities can become life-threatening. The primary cause of this toxicity is a deficiency in the enzyme Dihydropyrimidine Dehydrogenase (DPD), critical for metabolizing 5-FU. Variants in the DPYD gene, which encodes DPD, reduce or lose the enzyme activity of DPD. Patients with DPD enzyme deficiency are at great risk of severe toxicity. In this study, we validated and implemented the DPYD genotyping assay for cancer patients in Saskatchewan, Canada, to guide fluoropyrimidine dosing. We further assessed the clinical outcome post-implementation in Saskatchewan. Methods Six clinically relevant variants of the DPYD gene associated with DPD deficiency recommended by the 2017 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline were included in the assay (transcript NM_000110.4), including *2A (rs3918290; c.1905+1G&amp;gt;A), *13 (rs55886062; c.1679T&amp;gt;G), c.2846A&amp;gt;T (rs67376798), and c.1129-5923C&amp;gt;G (rs75017182). The HapB3 haplotype was assessed by the c.1129-5923C&amp;gt;G (rs75017182) variant in combination with c.1236G&amp;gt;A (rs56038477) and c.483+18G&amp;gt;A (rs56276561). The Elucigene DPYD genotyping kit (Yourgene Health, UK) was used to detect these six semi-qualitatively. The validation process follows the technical standards for clinical pharmacogenomic testing and reporting established by the American College of Medical Genetics and Genomics. The assay*s sensitivity, specificity, accuracy, repeatability and reproducibility in detecting DPYD variants were included. Six months post-implementation of DPYD genotyping assays, patient outcomes were retrospectively evaluated. Patient demographics and clinical data were collected, including tumour types and staging, treatment regimen and dosage adjustment based on DPYD genotyping lab results, and toxicity incidence. This study adhered to institutional ethics guidelines. Results The DPYD pharmacogenomic assay demonstrated excellent performance with 100% sensitivity, specificity, accuracy, reproducibility, and repeatability. The detection limit was 1.25 ng/µL of DNA, ensuring high sensitivity. Over six months, 301 patient samples were tested, identifying 22 patients carrying at least one of the six DPYD variants. The most frequently observed allele was the HapB3 heterozygous genotype detected in 18 patients (5.9%). All detected variants exhibited reduced function or no function, with assigned DPD activity scores ranging from 1 to 1.5, indicating impaired fluoropyrimidines metabolism. Outcomes were evaluated for 21 enzyme-deficient patients, with 5-FU dose adjustments applied clinically. The majority of patients tolerate chemotherapy well without significant toxicity. Outcome evaluation for the 301 tested patients is ongoing. Conclusion DPYD testing allows for the early detection of DPD deficiencies, allowing personalized chemo drug dosing. These approaches improve patient outcomes and reduce the risk of severe side effects, highlighting the important roles in pharmacogenomics in personalized cancer treatment.

Introduction: Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare but clinically significant genetic disorder that impairs the metabolism of 5-fluorouracil (5-FU), a cornerstone chemotherapeutic agent in gastrointestinal (GI) cancers. DPD normally inactivates 5-FU for safe excretion; deficiency can result in drug accumulation and potentially fatal toxicity. While most patients tolerate 5-FU, 10–40% experience grade ≥3 toxicities, primarily hematologic and gastrointestinal and 1% suffer fatal outcomes. Case Description/Methods: A 76-year-old woman with a history of gastric banding, gastroesophageal reflux disease, and Barrett’s esophagus was diagnosed with poorly differentiated esophageal adenocarcinoma during an diagnostic esophagogastroduodenoscopy for weight loss and anorexia. Imaging showed no metastasis, likely stage T2N0M0 and she began neoadjuvant FOLFOX chemotherapy (5-FU, leucovorin, oxaliplatin) in preparation for surgical resection. Ten days after the first cycle, she presented with generalized weakness and profuse diarrhea. Symptoms began on day 3 post-chemotherapy with severe mucositis, nausea, vomiting, and diarrhea. By day 11, she was in shock and required ICU care. She was found to have grade 4 mucositis, leukopenia (WBC 0.3 K/µL, ANC 0), and thrombocytopenia (platelets 25 K/µL). She was treated with vasopressors, G-CSF, transfusions, and broad-spectrum antibiotics. Infectious workup, including C. difficile and other enteric pathogens, was negative and sepsis was ultimately ruled out. Given the extreme toxicity after a single dose of 5-FU, DPD deficiency was suspected. Genetic testing confirmed heterozygosity for the non-functional DPYD*13 variant (activity score 1), indicating an intermediate metabolizer phenotype and increased risk for fluoropyrimidine toxicity. Her hospital course was further complicated by Hand-Foot-Mouth disease and a small bowel obstruction, both managed conservatively. She was discharged after 25 days. This case highlights the importance of DPD testing before 5-FU therapy. Discussion: GI cancers make up 25% of U.S. cancer cases and 35% of related deaths. Fluoropyrimidines like 5-FU and capecitabine remain key treatments, but can cause severe toxicity in patients with DPD deficiency. While European countries mandate cost-effective DPYD testing, U.S. guidelines currently suggest only shared decision-making. DPYD testing is a simple blood test. Gastroenterologists, often first to diagnose GI cancers and manage related toxicities, are uniquely positioned to advocate for testing.

913eTiP PRODIGE 91_UCGI 46_TRIFLUOX-DP: Trifluridine/Tipiracil (T/T) as replacement of fluoropyrimidines based chemotherapy as first-line metastatic colorectal or gastroesophageal cancer regimens in patients with dihydropyrimidine dehydrogenase deficiency (DPD) (an phase II trial)

Trifluridine/tipiracil (FTD/TPI) is approved for metastatic colorectal cancer as monotherapy or in combination with bevacizumab, though dosing in combination with oxaliplatin has not yet been established. The objective of the phase II SHORT trial (NCT04417699) was to determine the efficacy of short-course radiation (SC RT) followed by 3 months of FTD/TPI + oxaliplatin (TASOX) as a condensed total neoadjuvant therapy (TNT) regimen for intermediate-risk rectal cancer. Eligible patients with clinical T3N0 or T1-3N1 nonlow rectal tumors and negative radial tumor margins (>1 mm) were enrolled. The primary endpoint was reduction in neoadjuvant response (NAR) score compared with historic controls. Patients received 25 Gy in five 5 Gy fractions of conformal pelvic radiation followed by six planned 14-day cycles of TASOX: FTD/TPI (35 mg/m2/dose) orally b.i.d. day 1-5, oxaliplatin 85 mg/m2 i.v. day 1. Surgery was recommended within 4 weeks after cycle 6 of TASOX. Between 2020 and 2023, 13 patients with stage II (n = 5) and III (n = 8) rectal adenocarcinoma were enrolled at three institutions. Dose delivered was 100% of planned radiation, 99% of planned FTD/TPI and 95% oxaliplatin. Diarrhea was documented with a frequency of 11%, and was grade 1 only. Only 9% (8/87) of adverse events were grade 3/4, predominantly related to neutropenia. Among 10 patients who proceeded to total mesorectal excision surgery, 2 experienced a pathological complete response and 2 had a complete clinical response, of which 1 had no evidence of regrowth on continued watch and wait. SC RT and 3 months of TASOX can be safely delivered to patients with intermediate-risk rectal cancer, offering a convenient regimen that should be further explored for rectal cancer treatment. The TASOX regimen may be of particular relevance for patients with suspected dihydropyrimidine dehydrogenase deficiency who require oxaliplatin-based therapy.

Fluoropyrimidine derivatives can cause severe toxicity in patients with DPD deficiency. Regulatory agencies, such as the European Medicines Agency (EMA), recommend pre-emptive genotyping of the HapB3 haplotype, along with other variants. Historically, the two main HapB3 variants, the benign c.1236G>A and the pathogenic c.1129-5923C>G, have been assumed to be in complete linkage disequilibrium. Recent findings contradict this assumption, questioning the reliability of the HapB3 analysis through c.1236G>A, which could directly impact patient safety. The aim of this study is to assess the linkage disequilibrium between the c.1236G>A and c.1129-5923C>G variants, with the ultimate goal of revising genotyping guidelines. A total of 46 patients already heterozygous for the c.1236G>A variant have been carefully reviewed for the c.1129-5923C>G variant. From the 46 patients analyzed, 45 maintain complete linkage disequilibrium between both variants. However, there is one patient where this linkage disequilibrium is not complete, being heterozygous for c.1236G>A and homozygous for c.1129-5923C>G. These findings challenge the validity of c.1236G>A as a surrogate marker for pathogenic variant c.1129-5923C>G. This article highlights the need for a review of the recommendations of the EMA and suggests laboratories to analyze both variants, or at least the pathogenic one, to ensure accurate therapeutic decisions.

To assess the impact and outcomes of a novel program for routine preemptive DPYD testing in fluoropyrimidine (FP)-naïve patients. This single-center, retrospective cohort study included adult patients who either received a systemic FP or had a DPYD test result between July 1, 2022, and June 30, 2023. Patients were categorized into preemptive or standard cohorts on the basis of the timing of their DPYD test relative to their initial FP dose. Primary outcomes measured were 90-day all-cause mortality, and FP-related hospitalizations and emergency department (ED) visits after the first FP dose. Secondary outcomes included the incidence of empiric dose reductions, FP avoidance, and dose escalation tolerability among patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Among 1,281 patients, 90-day all-cause mortality was 5.78% in the preemptive cohort versus 8.23% in the standard cohort (adjusted hazard ratio [HR], 0.69 [95% CI, 0.43 to 1.10]; P = .12), with a notable overrepresentation of patients treated with curative intent in the preemptive group (53.0% v 39.4%, P < .0001). Deaths attributed to DPD deficiency were one (0.18%) in the preemptive cohort and four (0.72%) in the standard cohort (not statistically significant with limited power). Hospitalizations and ED visits related to FP toxicity were paradoxically higher in the preemptive cohort (13.99% v 8.69%, adjusted HR, 1.67 [95% CI, 1.15 to 2.43]; P = .007). Among patients with DPD deficiency in the preemptive cohort, 84.6% received an empiric FP dose reduction, and dose escalation was attempted in 52.2% of these cases. Preemptive DPYD testing did not significantly reduce treatment-related mortality, although a numerical decrease suggests potential benefits that may be substantiated with greater statistical power. Nearly half of the patients managed with a dose reduction did not undergo dose escalation.

1618 Background: DPD deficiency is the most important risk factor for developing fluoropyrimidine-related adverse events. Genetic variants causing DPD deficiency are found in 6-8% of Caucasian patients. However, there is limited information on their prevalence in underrepresented ethnic groups, such as Hispanics and Latinos, and testing for these variants is not routinely recommended in Latin America. Our goal was to assess the allele frequency of clinically actionable dihydropyrimidine dehydrogenase ( DPYD) risk variants defined by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the European Medicines Agency (EMA) among admixed Mexican patients with GI malignancies. Methods: Patients with recently diagnosed GI cancer candidates for fluropyrimidine therapy were recruited from a single institution in Mexico City. After providing informed consent, a blood sample and clinical characteristics were collected. We utilized the Illumina Infinium Global Screening Array (GSA)-to genotype 34 DPYD variants, six of which are known to lead to an increased risk of fluoropyrimidine toxicity and are considered clinically actionable. Results: Two hundred and eight patients with a mean age of 62 years (SD 13.2) were included. 47% were female. The most common type of cancer was colorectal (38%) followed by pancreas (22%) and biliary tract (18%). DNA samples from 192 patients passed quality control, of which 156 (62%) received fluoropyrimidines during follow-up. Only 2 patients (1%) were heterozygous for actionable DPYD intermediate metabolizer risk variant alleles: one with c.2846A &gt; T ( rs67376798 , D949V) and one with c.1129–5923C &gt; G [ rs75017182; HapB3 SNP c.1236G &gt; A; rs56038477]. No patients were found to have other CPIC-listed DPYD risk variants . Additionally, we investigated the allele frequencies of other 30 DPYD variants and observed low-frequency variation (between 0.260 and 0.0032) in rs56038477, rs1801160, rs17376848, rs1801159, rs1801158, rs45589337, rs2297595, rs200562975, and rs1801265. Several of these may be related to decreased DPYD activity and warrant further analysis regarding their impact on adverse drug reactions. Conclusions: In contrast with reports from Caucasic populations, we found a very low allele frequency of DPYD actionable variants. Our findings highlight the limitation of current pharmacogenomic testing recommendations and panels, which may not be appropriate for admixed ethnic populations such as Hispanics/Latinos due to disparities in representation. There is a need to study the role of other DPYD variants in larger patient samples to understand their role in the toxicity risk of admixed populations in Mexico and Latin America, to explore the use of novel techniques such as Next Generation Sequencing, and to investigate the effect of other related genes on toxicity risk.

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 &gt; 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 &gt; A), not the causative deep intronic variant (c.1129-5923C &gt; 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.