Importance of and Strategies for Implementing DPYD Testing to Prevent Severe Fluoropyrimidine Chemotherapy Toxicity in Health Care Systems.

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

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels.Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide.Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%.Conclusion:DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

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 .

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

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.

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)

451 Background: Variants in the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD), are associated with impaired metabolism of fluoropyrimidines including fluorouracil (5-FU) and its oral prodrug, capecitabine. Patients with these variants are at increased risk for severe and potentially life-threatening toxicities. In December 2022, Dana-Farber Cancer Institute (DFCI) implemented a standardized, institution-wide program to support preemptive DPYD genotyping and genotype-guided dosing for patients initiating fluoropyrimidine-based therapy. The initiative included automated electronic health record prompts, pharmacist-led genotype-based dosing recommendations, as well as provider, pharmacist, nurse, and patient education. Methods: In September 2024, a new pharmacist-driven workflow was launched to enhance re-escalation rates in patients undergoing dose reduction based on DPYD genotyping and to operationalize genotype-guided dose initiation and adjustment in the outpatient setting. The workflow includes systematic identification of patients without prior exposure to 5-fluorouracil (5-FU) or capecitabine, automated prompts for DPYD testing, and a closed-loop notification system for abnormal results. Pharmacists provide dose modification and re-escalation recommendations based on standardized guidelines. The process also includes structured documentation and tracking of genotyping results and corresponding dose recommendations. Targeted training was delivered to clinical staff to ensure consistent adoption and adherence to the workflow. Results: Following the implementation of the pharmacist-driven DPYD workflow, DPYD gene deficiencies were identified in 28 patients receiving 5-fluorouracil and 17 patients receiving capecitabine out of the 810 patients that were tested from September 2024 to May 2025. Pharmacist-led genotype-guided dose reduction recommendations were provided for all identified patients, with 40/45 recommendations accepted by oncologist. Among these,14 patients were dose re-escalated based on clinical tolerability and in accordance with the standardized dosing recommendations. Conclusions: The implementation of a pharmacist-driven workflow for DPYD genotype interpretation and dose recommendations is both feasible and impactful in the outpatient oncology setting. This proactive approach supports personalized chemotherapy dosing, potentially reducing both the risk of over- and undertreatment.

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

Since April 2020, pretherapeutic screening for accessing the deficiency of the DPD enzyme by genotyping the dihydropyrimidine dehydrogenase gene (DPYD) is required by the European Medicine Agency (EMA) prior to the administration of fluoropyrimidine-based chemotherapy. In May 2020, the Spanish Drug and Medical Devices Agency (AEMPS) published an informative note highlighting the importance of DPYD analysis prior fluoropyrimidines derivatives administration to prevent the development of severe adverse drug reactions (ADRs). The publication of these recommendations marked a turning point in the daily routine in many pharmacogenetics laboratories in Spain. This article aims to illustrate the current state of the DPYD testing in the reference genomic medicine center in Galicia, 4years after the EMA's updated recommendations. The Pharmacogenetics Unit in the reference genomic medicine center conducted genotyping of the four DPYD variants recommended by regulatory agencies that oncologists can adjust fluoropyrimidine treatment based on DPYD genotype results. Between 1 June 2020 to 1 May 2024, both included, a total of 2,798 DPYD requests were analyzed. DPYD genotyping results revealed a 3.15% prevalence of heterozygosity for at least one of the four DPYD variants, being rs56038477 the most prevalent variant (1.31%). This study addresses the importance of the DPYD analysis implementation in clinical practice after the changes in EMA and AEMPs recommendations which has led to a significant increase in DPYD genotyping requests. This highlights the significance of preemptive genotyping for accurately adjusting fluoropyrimidines doses before initiating treatment.

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10days of ordering. Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Purpose Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. Methods From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. Results Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the 4 or 5 DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. Conclusion Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Introduction: Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. DPYD gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. DPYD variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on DPYD genotyping. The aim of the present study was to analyze prevalence of DPYD rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients.Methods: Study group consisted of 313 FP-treated cancer patients. DPYD genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160).Results: Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. DPYD EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (p = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, p = 0.004, 97.9% specificity). DPYD deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, p = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, p = 0.014), neurological (OR: 4.134, p = 0.040) and nutrition/metabolism (OR: 4.821, p = 0.035) toxicities. FP dose intensity was significantly reduced in DPYD deficient patients (β = −0.060, p <0.001). DPYD rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of DPYD*TYMS*MTHFR was associated with grade 3-4 toxicity (OR: 3.725, p = 0.007).Conclusion: Our findings confirm the clinical validity of DPYD reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment DPYD genotyping should be implemented in clinical practice and guide FP dosing. DPYD*gene interactions merit further investigation as to their potential to increase the prognostic value of DPYD genotyping and improve safety of FP-based chemotherapy.

To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Our results indicate that a combined genotype-phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes.