RARE DISEASE
Dihydropyrimidine dehydrogenase deficiency
Dihydropyrimidine dehydrogenase deficiency
Dihydropyrimidine dehydrogenase deficiency
Synonyms: Familial pyrimidinemia
Synonyms: Familial pyrimidinemia
Synonyms: Familial pyrimidinemia
Drug discovery
1
drug
With orphan designation
Overview
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder impairing pyrimidine metabolism due to DPYD gene mutations. It causes toxic accumulation of thymine/uracil and severe fluoropyrimidine (5-FU/capecitabine) toxicity due to reduced drug detoxification. Clinical manifestations range from asymptomatic carriers to neurodevelopmental delays, seizures, and microcephaly in severe cases [1][2][6]. Pre-treatment screening is critical to mitigate life-threatening adverse drug reactions [6][13].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
235 drug discovery papers about Dihydropyrimidine dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
235 drug discovery papers about Dihydropyrimidine dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-23 | Dihydropyrimidine dehydrogenase phenotype-guided dose individualization of fluoropyrimidine in gastrointestinal cancers: PRODIGE100-UCGI48-FUDOSE phase II study.
Pre-treatment screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on plasma uracil concentration ([U]) is mandatory in France before fluoropyrimidine (FP) administration. However, dose-adjustment strategies according to [U] in case of partial DPD deficiency remain empirical, heterogeneous across centers and lacking clear recommendations. This national, multicenter, open-label phase II trial will enroll approximately 400 patients schedule to receive FP-based chemotherapy combined with oxaliplatin, with or without targeted therapy. Patients will be stratified by pre-treatment [U] into one control arm (non-DPD-deficient, [U] <16 ng/mL) receiving a full standard FP starting dose, and four DPD-deficient cohorts ([16-20[, [20-50[, [50-100[, and [100-150[ ng/mL) receiving prespecified starting dose. The primary endpoint is FP-induced grade ≥3 hematological and gastrointestinal toxicity during the first two treatment cycles, compared between DPD-deficient cohorts vs control arm within a Bayesian framework. Interim analyses with sequential toxicity monitoring are planned to allow protocol adaptation if safety concerns arise. Secondary endpoints include overall toxicity profiles, dose adaptations, survival outcomes, pharmacokinetic analyses, and correlations between [U] levels and DPYD genotypes. This trial addresses a major gap between mandatory preemptive DPD phenotyping and actionable FP dosing recommendations, to generate prospective evidence supporting safer and harmonized FP use in routine clinical practice. FUDOSE is registered at Clinicaltrials.gov (NCT06475352).
2026-05-03 | Dabupi decoction mitigates fluorouracil-induced intestinal mucositis via farnesoid X receptor activation and dihydropyrimidine dehydrogenase upregulation.
5-Fluorouracil (5-FU) is a widely utilized antimetabolite in colorectal cancer chemotherapy, primarily exerting its cytotoxic effects by irreversibly inhibiting thymidylate synthase (TS). This inhibition leads to a reduction in deoxythymidine monophosphate (dTMP), which disrupts DNA synthesis and repair. A major challenge in 5-FU treatment is the dose-limiting toxicity of chemotherapeutic-induced intestinal mucositis. Da-Bu-Pi Decoction (DBPD), a well-established formula in traditional Chinese medicine for treating spleen-stomach deficiency, is often used to enhance spleen qi and balance the middle jiao. While growing clinical evidence points to the therapeutic benefits of DBPD in alleviating 5-FU-induced mucositis, the underlying molecular mechanisms remain largely undefined. To elucidate the molecular mechanisms underlying chemotherapy-induced intestinal mucositis (CIM) induced by 5-FU, with a focus on the disruption of bile acid metabolism and the downregulation of the key detoxifying enzyme DPYD expression. DBPD was administered orally to C57BL/6 mice with 5-FU-induced intestinal mucositis over a seven-day period. The evaluation of intestinal damage included assessments of diarrhea, morphology, intestinal barrier function and inflammatory factors, alongside techniques such as immunofluorescence, immunohistochemistry, transmission electron microscopy and Western blot. Transcriptome analysis of mouse ileal tissue was applied to reveal differentially expressed genes (DEGs) in different treated mice, and bile acid metabolism-related genes (UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A9, Farnesoid x receptor (FXR), TGR5) and DPYD, a key detoxification enzyme for 5-FU, were confirmed by qRT-PCR. Additionally, changes of DCA and LCA were measured using ELISA. Bioinformatics helped delineate the association of these genes with pan-cancer versus normal tissues. Meanwhile, 5-FU-induced intestinal epithelial cells (HIEC) were treated with serum containing DBPD. It was further explored how DBPD modulates the UGT1A1/TGR5/FXR signaling pathway and enhances DPYD activity to reduce apoptosis and intestinal barrier damage in 5-FU induced HIEC. AlphaFold3 and further bioinformatics analysis predicted the binding interactions and expression correlations among UGT1A1, UGT1A9 and FXR. DBPD is protective by reducing inflammation and intestinal barrier dysfunction in 5-FU-induced intestinal mucositis. Transcriptome analysis and in vivo validation highlighted the crucial function of bile acid metabolism-related pathways and DPYD in 5-FU-induced CIM. 5-FU increased the levels of deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse ileum. DBPD activated the UGT1A1/TGR5/FXR pathway and up-regulated DPYD to suppress the pathological accumulation of these specific cytotoxic bile acids within the local intestinal microenvironment and ameliorate 5-FU-induced CIM. It was indicated by the analysis of bioinformatics that low levels of UGT1A1, UGT1A9, and FXR exhibited a connection with poor prognosis within colorectal cancer. In vitro studies confirmed that DBPD significantly improved the UGT1A1/TGR5/FXR pathway and increased the expression of DPYD in 5-FU treated HIEC, thereby improving intestinal barrier integrity and alleviating apoptosis. Further validation using the FXR inhibitor (Gly-β-MCA) showed that DBPD ameliorated Gly-β-MCA induced HIEC apoptosis and barrier attenuation. Finally, AlphaFold3 and bioinformatics predictions suggested potential binding interactions between UGT1A1, UGT1A9 and FXR with positively correlated expression.
2026-03-09 | DPYD genotyping in patients receiving capecitabine: an exploratory analysis from the D-TORCH study.
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.
2026-02-06 | Results of a phase II trial of short-course radiation and TASOX [trifluridine/tipiracil (TAS-102) plus oxaliplatin] chemotherapy in operable rectal cancer.
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.
2026-02-04 | Clinical response to capecitabine in a DPYD*2A homozygous patient: Case report and therapeutic guidance.
Complete dihydropyrimidine dehydrogenase (DPD) deficiency due to homozygous DPYD*2A is a contraindication for fluoropyrimidines because of the extreme risk of life-threatening toxicity. We report a 36-year-old male with metastatic rectal adenocarcinoma and complete DPD deficiency who received ultra-low-dose capecitabine in combination with oxaliplatin and cetuximab. Initial dosing of capecitabine 150 mg on Days 1, 6 and 16 of a 21-day cycle (0.76% of the BSA-based standard regimen) caused Grade 3 mucositis, but further dose reduction to capecitabine 150 mg on Days 1 and 8 of a 21-day cycle (0.50%) improved tolerability. Pharmacokinetic analyses revealed markedly prolonged 5-fluorouracil exposure with undetectable fluoro-β-alanine (FBAL), consistent with complete DPD deficiency. Despite the minimal dosing, a near-complete metabolic response was achieved after four cycles, enabling surgical resection of residual disease. This case illustrates that carefully individualized ultra-low-dose capecitabine, guided by pharmacokinetics and toxicity monitoring, can provide meaningful clinical benefit in patients with complete DPD deficiency. These findings highlight the therapeutic potential of a precision dosing approach in this rare but clinically challenging setting.
gene therapies
2026-05-28 | NGS-based DPYD diplotype analysis beyond conventional targeted variant testing in an ethnically diverse cancer patient cohort.
e15131 Background: Germline variants in the highly polymorphic DPYD gene are the main cause of dihydropyrimidine dehydrogenase (DPD) deficiency and are strongly associated with fluoropyrimidine-related toxicity. PCR-based assays test limited predefined variants and may miss clinically relevant alleles, particularly in ethnically diverse populations. Next-generation sequencing (NGS) allows broader and comprehensive assessment of DPYD variation. Methods: This retrospective study included 4,380 diagnosed cancer patients of Caucasian and non-Caucasian ancestry undergoing routine DPYD testing using NGS-based profiling with the Shield assay at Datar Cancer Genetics. Identified variants were translated into diplotypes and assigned activity scores according to CPIC and DPWG guidelines, classifying patients as normal, intermediate, or poor metabolizers. Results: Clinically relevant DPYD variants associated with reduced or absent DPD activity were identified in 4.8% (211/4380) of patients, comprising 4.7% (n = 209) intermediate and 0.1% (n = 2) poor metabolizers. Reduced-function and no-function alleles detected in the cohort included *2A, HapB3, and c.557A>G, either in heterozygous or compound diplotype configurations. Intermediate metabolizer status was driven by diplotypes such as *9A/HapB3 and c.557A>G–containing combinations, reflecting the impact of a single reduced-function allele when paired with an otherwise normal allele. Poor metabolizer phenotypes were exclusively associated with biallelic or compound heterozygous diplotypes involving known no-function or severely reduced-function alleles, including *2A/*2A and HapB3/*2A. Notably, several clinically actionable diplotypes would not have been detected by assays limited to a small set of predefined variants, emphasizing the importance of comprehensive NGS-based DPYD profiling and diplotype-level interpretation for accurate phenotype assignment. Conclusions: Nearly 5% of patients were classified as intermediate or poor metabolizers, placing them at increased risk for severe fluoropyrimidine toxicity. Comprehensive NGS-based DPYD testing enables detection of both common and rare reduced-function variants, supports more accurate phenotype assignment, and provides a practical approach to safer fluoropyrimidine dosing in ethnically diverse clinical populations. Clinically actionable DPYD alleles identified by NGS. Allele Frequency Function HapB3 3.04% Reduced function allele *2A 0.91% Absent DPYD activity allele c.2846A>T 0.50% Reduced function allele c.2279C>T 0.23% Reduced function allele c.557A>G 0.11% Reduced function allele *4 3.45% Absent DPYD activity allele *13 0.07% Absent DPYD activity allele *3 0.02% Absent DPYD activity allele *8 0.02% Absent DPYD activity allele
2026-01-10 | DPYD genotype-guided dose personalization for fluoropyrimidine prescribing in Australia: GeneScreen 5-FU trial.
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 .
2026-01-10 | Association of uncommon DPYD polymorphisms with severe fluoropyrimidine toxicity.
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)
2025-10-01 | B-251 Clinical Implementation and Outcome Assessment of DPYD Pharmacogenomic Testing to Guide Fluoropyrimidines Dosing for Cancer Patients in Saskatchewan
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>A), *13 (rs55886062; c.1679T>G), c.2846A>T (rs67376798), and c.1129-5923C>G (rs75017182). The HapB3 haplotype was assessed by the c.1129-5923C>G (rs75017182) variant in combination with c.1236G>A (rs56038477) and c.483+18G>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.
2023-10-01 | S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma
Introduction: Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that metabolizes fluorouracil (5-FU). A mutation in its gene causes decreased activity of DPYD propagating 5-FU toxicity. The prevalence of this mutation is 3%-5% in the general population, and the most common variant is DPYD*2A. Patients with the mutation have a 50-60% risk of grade 3-4 5-FU toxicity (severe diarrhea, mucositis/stomatitis, neurotoxicity, skin changes, and pancytopenia). We present an exceedingly rare case of 5-FU toxicity in a colorectal adenocarcinoma patient with a DPYD*2A mutation. Case Description/Methods: A 53-year-old woman with a past medical history of Stage IIIB colorectal adenocarcinoma (loss of PMS2, partial loss of MLH1, and intact MSH2 and MSH6) post right hemicolectomy presented with an erythematous blanching rash on her chest, back, trunk, soles of hands and feet shortly after her first cycle of adjuvant modified FOLFOX infusion. She endorsed diarrhea, and odynophagia limiting oral intake. Epinephrine, dexamethasone, diphenhydramine and famotidine was given to assist with oral swelling. Clostridioides difficile testing was negative. She was started on nystatin oral suspension, intravenous fluconazole for esophageal candidiasis and topical clomitrazole, which did not provide relief. Therefore, intravenous dexamethasone 20 mg for 5 days was started. As Steven’s Johnsons remained on the differential, a punch biopsy of the left groin was performed, which showed systemic drug-related intertriginous and flexural exanthema. She was noted to be positive for a heterozygous DPYD *2A mutation. She experienced worsening intertriginous and flexural exanthema, palmoplantar erythema and neutropenia. Ultimately, the patient developed superimposed necrotizing fasciitis requiring antibiotics, antifungals and surgical debridement. The patient unfortunately continued to deteriorate, in septic shock requiring intensive care. She ultimately passed after opting for comfort care. Discussion: Our patient presented with many of the common symptoms associated with 5-FU toxicity, including Grade 4 mucositis and diarrhea in the setting of a DPD mutation. Currently from the National Cancer Comprehensive Network, there are no guidelines for pre-treatment DPD screening. Some barriers may include cost of screening, and potential delay to treatment. However, our case provides further evidence that screening of an albeit rare mutation could prevent toxicity, adverse outcomes, and decrease overall healthcare cost and burden with early detection.
oligonucleotides
2023-08-27 | Genetic Variation in miR-27a Is Associated with Fluoropyrimidine-Associated Toxicity in Patients with Dihydropyrimidine Dehydrogenase Variants after Genotype-Guided Dose Reduction
Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in DPYD only partially explain fluoropyrimidine-induced toxicity. The expression of DPYD has previously been shown to be regulated by microRNA-27a (miR-27a) and a common miR-27a SNV (rs895819) has been associated with an increased risk of toxicity in patients harboring a DPYD variant who received standard fluoropyrimidine dosing. We investigated if the miR-27a rs895819 SNV was associated with toxicity in DPYD wildtype patients and carriers of DPYD variants who received a reduced dose. The regulation of DPYD using miR-27a was investigated in HepG2 cells utilizing a miR-27a mimic. miR-27a overexpression decreased DPYD mRNA expression compared to control cells (p < 0.0001). In a cohort of patients that received pre-emptive DPYD genotyping, 45 patients had a DPYD variant and 180 were wildtype. Patients heterozygous for rs895819 had an increased risk of toxicity, which was seen in both patients who were wildtype for DPYD variants (OR (95%CI) = 1.99 (1.00-3.99)) and DPYD variant carriers (OR (95%CI) = 8.10 (1.16-86.21)). Therefore, miR-27a rs895819 may be a clinically relevant predictor of fluoropyrimidine-associated toxicities. Furthermore, toxicity was more profound in DPYD variant carriers, even after DPYD genotype-guided dose reduction. This suggests that patients may benefit from miR-27a genotyping to guide fluoropyrimidine dosing.
small molecules
2026-05-23 | Dihydropyrimidine dehydrogenase phenotype-guided dose individualization of fluoropyrimidine in gastrointestinal cancers: PRODIGE100-UCGI48-FUDOSE phase II study.
Pre-treatment screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on plasma uracil concentration ([U]) is mandatory in France before fluoropyrimidine (FP) administration. However, dose-adjustment strategies according to [U] in case of partial DPD deficiency remain empirical, heterogeneous across centers and lacking clear recommendations. This national, multicenter, open-label phase II trial will enroll approximately 400 patients schedule to receive FP-based chemotherapy combined with oxaliplatin, with or without targeted therapy. Patients will be stratified by pre-treatment [U] into one control arm (non-DPD-deficient, [U] <16 ng/mL) receiving a full standard FP starting dose, and four DPD-deficient cohorts ([16-20[, [20-50[, [50-100[, and [100-150[ ng/mL) receiving prespecified starting dose. The primary endpoint is FP-induced grade ≥3 hematological and gastrointestinal toxicity during the first two treatment cycles, compared between DPD-deficient cohorts vs control arm within a Bayesian framework. Interim analyses with sequential toxicity monitoring are planned to allow protocol adaptation if safety concerns arise. Secondary endpoints include overall toxicity profiles, dose adaptations, survival outcomes, pharmacokinetic analyses, and correlations between [U] levels and DPYD genotypes. This trial addresses a major gap between mandatory preemptive DPD phenotyping and actionable FP dosing recommendations, to generate prospective evidence supporting safer and harmonized FP use in routine clinical practice. FUDOSE is registered at Clinicaltrials.gov (NCT06475352).
2026-05-03 | Dabupi decoction mitigates fluorouracil-induced intestinal mucositis via farnesoid X receptor activation and dihydropyrimidine dehydrogenase upregulation.
5-Fluorouracil (5-FU) is a widely utilized antimetabolite in colorectal cancer chemotherapy, primarily exerting its cytotoxic effects by irreversibly inhibiting thymidylate synthase (TS). This inhibition leads to a reduction in deoxythymidine monophosphate (dTMP), which disrupts DNA synthesis and repair. A major challenge in 5-FU treatment is the dose-limiting toxicity of chemotherapeutic-induced intestinal mucositis. Da-Bu-Pi Decoction (DBPD), a well-established formula in traditional Chinese medicine for treating spleen-stomach deficiency, is often used to enhance spleen qi and balance the middle jiao. While growing clinical evidence points to the therapeutic benefits of DBPD in alleviating 5-FU-induced mucositis, the underlying molecular mechanisms remain largely undefined. To elucidate the molecular mechanisms underlying chemotherapy-induced intestinal mucositis (CIM) induced by 5-FU, with a focus on the disruption of bile acid metabolism and the downregulation of the key detoxifying enzyme DPYD expression. DBPD was administered orally to C57BL/6 mice with 5-FU-induced intestinal mucositis over a seven-day period. The evaluation of intestinal damage included assessments of diarrhea, morphology, intestinal barrier function and inflammatory factors, alongside techniques such as immunofluorescence, immunohistochemistry, transmission electron microscopy and Western blot. Transcriptome analysis of mouse ileal tissue was applied to reveal differentially expressed genes (DEGs) in different treated mice, and bile acid metabolism-related genes (UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A9, Farnesoid x receptor (FXR), TGR5) and DPYD, a key detoxification enzyme for 5-FU, were confirmed by qRT-PCR. Additionally, changes of DCA and LCA were measured using ELISA. Bioinformatics helped delineate the association of these genes with pan-cancer versus normal tissues. Meanwhile, 5-FU-induced intestinal epithelial cells (HIEC) were treated with serum containing DBPD. It was further explored how DBPD modulates the UGT1A1/TGR5/FXR signaling pathway and enhances DPYD activity to reduce apoptosis and intestinal barrier damage in 5-FU induced HIEC. AlphaFold3 and further bioinformatics analysis predicted the binding interactions and expression correlations among UGT1A1, UGT1A9 and FXR. DBPD is protective by reducing inflammation and intestinal barrier dysfunction in 5-FU-induced intestinal mucositis. Transcriptome analysis and in vivo validation highlighted the crucial function of bile acid metabolism-related pathways and DPYD in 5-FU-induced CIM. 5-FU increased the levels of deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse ileum. DBPD activated the UGT1A1/TGR5/FXR pathway and up-regulated DPYD to suppress the pathological accumulation of these specific cytotoxic bile acids within the local intestinal microenvironment and ameliorate 5-FU-induced CIM. It was indicated by the analysis of bioinformatics that low levels of UGT1A1, UGT1A9, and FXR exhibited a connection with poor prognosis within colorectal cancer. In vitro studies confirmed that DBPD significantly improved the UGT1A1/TGR5/FXR pathway and increased the expression of DPYD in 5-FU treated HIEC, thereby improving intestinal barrier integrity and alleviating apoptosis. Further validation using the FXR inhibitor (Gly-β-MCA) showed that DBPD ameliorated Gly-β-MCA induced HIEC apoptosis and barrier attenuation. Finally, AlphaFold3 and bioinformatics predictions suggested potential binding interactions between UGT1A1, UGT1A9 and FXR with positively correlated expression.
2026-03-09 | DPYD genotyping in patients receiving capecitabine: an exploratory analysis from the D-TORCH study.
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.
2026-02-06 | Results of a phase II trial of short-course radiation and TASOX [trifluridine/tipiracil (TAS-102) plus oxaliplatin] chemotherapy in operable rectal cancer.
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.
2026-02-04 | Clinical response to capecitabine in a DPYD*2A homozygous patient: Case report and therapeutic guidance.
Complete dihydropyrimidine dehydrogenase (DPD) deficiency due to homozygous DPYD*2A is a contraindication for fluoropyrimidines because of the extreme risk of life-threatening toxicity. We report a 36-year-old male with metastatic rectal adenocarcinoma and complete DPD deficiency who received ultra-low-dose capecitabine in combination with oxaliplatin and cetuximab. Initial dosing of capecitabine 150 mg on Days 1, 6 and 16 of a 21-day cycle (0.76% of the BSA-based standard regimen) caused Grade 3 mucositis, but further dose reduction to capecitabine 150 mg on Days 1 and 8 of a 21-day cycle (0.50%) improved tolerability. Pharmacokinetic analyses revealed markedly prolonged 5-fluorouracil exposure with undetectable fluoro-β-alanine (FBAL), consistent with complete DPD deficiency. Despite the minimal dosing, a near-complete metabolic response was achieved after four cycles, enabling surgical resection of residual disease. This case illustrates that carefully individualized ultra-low-dose capecitabine, guided by pharmacokinetics and toxicity monitoring, can provide meaningful clinical benefit in patients with complete DPD deficiency. These findings highlight the therapeutic potential of a precision dosing approach in this rare but clinically challenging setting.
gene therapies
2026-05-28 | NGS-based DPYD diplotype analysis beyond conventional targeted variant testing in an ethnically diverse cancer patient cohort.
e15131 Background: Germline variants in the highly polymorphic DPYD gene are the main cause of dihydropyrimidine dehydrogenase (DPD) deficiency and are strongly associated with fluoropyrimidine-related toxicity. PCR-based assays test limited predefined variants and may miss clinically relevant alleles, particularly in ethnically diverse populations. Next-generation sequencing (NGS) allows broader and comprehensive assessment of DPYD variation. Methods: This retrospective study included 4,380 diagnosed cancer patients of Caucasian and non-Caucasian ancestry undergoing routine DPYD testing using NGS-based profiling with the Shield assay at Datar Cancer Genetics. Identified variants were translated into diplotypes and assigned activity scores according to CPIC and DPWG guidelines, classifying patients as normal, intermediate, or poor metabolizers. Results: Clinically relevant DPYD variants associated with reduced or absent DPD activity were identified in 4.8% (211/4380) of patients, comprising 4.7% (n = 209) intermediate and 0.1% (n = 2) poor metabolizers. Reduced-function and no-function alleles detected in the cohort included *2A, HapB3, and c.557A>G, either in heterozygous or compound diplotype configurations. Intermediate metabolizer status was driven by diplotypes such as *9A/HapB3 and c.557A>G–containing combinations, reflecting the impact of a single reduced-function allele when paired with an otherwise normal allele. Poor metabolizer phenotypes were exclusively associated with biallelic or compound heterozygous diplotypes involving known no-function or severely reduced-function alleles, including *2A/*2A and HapB3/*2A. Notably, several clinically actionable diplotypes would not have been detected by assays limited to a small set of predefined variants, emphasizing the importance of comprehensive NGS-based DPYD profiling and diplotype-level interpretation for accurate phenotype assignment. Conclusions: Nearly 5% of patients were classified as intermediate or poor metabolizers, placing them at increased risk for severe fluoropyrimidine toxicity. Comprehensive NGS-based DPYD testing enables detection of both common and rare reduced-function variants, supports more accurate phenotype assignment, and provides a practical approach to safer fluoropyrimidine dosing in ethnically diverse clinical populations. Clinically actionable DPYD alleles identified by NGS. Allele Frequency Function HapB3 3.04% Reduced function allele *2A 0.91% Absent DPYD activity allele c.2846A>T 0.50% Reduced function allele c.2279C>T 0.23% Reduced function allele c.557A>G 0.11% Reduced function allele *4 3.45% Absent DPYD activity allele *13 0.07% Absent DPYD activity allele *3 0.02% Absent DPYD activity allele *8 0.02% Absent DPYD activity allele
2026-01-10 | DPYD genotype-guided dose personalization for fluoropyrimidine prescribing in Australia: GeneScreen 5-FU trial.
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 .
2026-01-10 | Association of uncommon DPYD polymorphisms with severe fluoropyrimidine toxicity.
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)
2025-10-01 | B-251 Clinical Implementation and Outcome Assessment of DPYD Pharmacogenomic Testing to Guide Fluoropyrimidines Dosing for Cancer Patients in Saskatchewan
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>A), *13 (rs55886062; c.1679T>G), c.2846A>T (rs67376798), and c.1129-5923C>G (rs75017182). The HapB3 haplotype was assessed by the c.1129-5923C>G (rs75017182) variant in combination with c.1236G>A (rs56038477) and c.483+18G>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.
2023-10-01 | S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma
Introduction: Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that metabolizes fluorouracil (5-FU). A mutation in its gene causes decreased activity of DPYD propagating 5-FU toxicity. The prevalence of this mutation is 3%-5% in the general population, and the most common variant is DPYD*2A. Patients with the mutation have a 50-60% risk of grade 3-4 5-FU toxicity (severe diarrhea, mucositis/stomatitis, neurotoxicity, skin changes, and pancytopenia). We present an exceedingly rare case of 5-FU toxicity in a colorectal adenocarcinoma patient with a DPYD*2A mutation. Case Description/Methods: A 53-year-old woman with a past medical history of Stage IIIB colorectal adenocarcinoma (loss of PMS2, partial loss of MLH1, and intact MSH2 and MSH6) post right hemicolectomy presented with an erythematous blanching rash on her chest, back, trunk, soles of hands and feet shortly after her first cycle of adjuvant modified FOLFOX infusion. She endorsed diarrhea, and odynophagia limiting oral intake. Epinephrine, dexamethasone, diphenhydramine and famotidine was given to assist with oral swelling. Clostridioides difficile testing was negative. She was started on nystatin oral suspension, intravenous fluconazole for esophageal candidiasis and topical clomitrazole, which did not provide relief. Therefore, intravenous dexamethasone 20 mg for 5 days was started. As Steven’s Johnsons remained on the differential, a punch biopsy of the left groin was performed, which showed systemic drug-related intertriginous and flexural exanthema. She was noted to be positive for a heterozygous DPYD *2A mutation. She experienced worsening intertriginous and flexural exanthema, palmoplantar erythema and neutropenia. Ultimately, the patient developed superimposed necrotizing fasciitis requiring antibiotics, antifungals and surgical debridement. The patient unfortunately continued to deteriorate, in septic shock requiring intensive care. She ultimately passed after opting for comfort care. Discussion: Our patient presented with many of the common symptoms associated with 5-FU toxicity, including Grade 4 mucositis and diarrhea in the setting of a DPD mutation. Currently from the National Cancer Comprehensive Network, there are no guidelines for pre-treatment DPD screening. Some barriers may include cost of screening, and potential delay to treatment. However, our case provides further evidence that screening of an albeit rare mutation could prevent toxicity, adverse outcomes, and decrease overall healthcare cost and burden with early detection.
oligonucleotides
2023-08-27 | Genetic Variation in miR-27a Is Associated with Fluoropyrimidine-Associated Toxicity in Patients with Dihydropyrimidine Dehydrogenase Variants after Genotype-Guided Dose Reduction
Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in DPYD only partially explain fluoropyrimidine-induced toxicity. The expression of DPYD has previously been shown to be regulated by microRNA-27a (miR-27a) and a common miR-27a SNV (rs895819) has been associated with an increased risk of toxicity in patients harboring a DPYD variant who received standard fluoropyrimidine dosing. We investigated if the miR-27a rs895819 SNV was associated with toxicity in DPYD wildtype patients and carriers of DPYD variants who received a reduced dose. The regulation of DPYD using miR-27a was investigated in HepG2 cells utilizing a miR-27a mimic. miR-27a overexpression decreased DPYD mRNA expression compared to control cells (p < 0.0001). In a cohort of patients that received pre-emptive DPYD genotyping, 45 patients had a DPYD variant and 180 were wildtype. Patients heterozygous for rs895819 had an increased risk of toxicity, which was seen in both patients who were wildtype for DPYD variants (OR (95%CI) = 1.99 (1.00-3.99)) and DPYD variant carriers (OR (95%CI) = 8.10 (1.16-86.21)). Therefore, miR-27a rs895819 may be a clinically relevant predictor of fluoropyrimidine-associated toxicities. Furthermore, toxicity was more profound in DPYD variant carriers, even after DPYD genotype-guided dose reduction. This suggests that patients may benefit from miR-27a genotyping to guide fluoropyrimidine dosing.
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Drug Discovery Landscape
1 orphan drug designation for Dihydropyrimidine dehydrogenase deficiency.
1 orphan drug designation for Dihydropyrimidine dehydrogenase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid | — | FDA | 2022-01-06 | — | Applied Therapeutics Inc. |
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