5PSQ-130 Impact of DPYD gene polymorphisms and toxicity on fluoropyrimidine treatment

<h3>Background and Importance</h3> Fluoropyrimidines (FU), such as 5-fluorouracil and capecitabine, are cytostatic agents with a narrow therapeutic range. Approximately 80–90% of administered FU is metabolised by the enzyme dihydropyrimidine dehydrogenase (DPD), and its deficiency can cause severe toxicity or even death. <h3>Aim and Objectives</h3> To describe polymorphisms in the DPYD gene and toxicity in these patients in two tertiary hospitals and evaluate the level of acceptance of the recommendations from Pharmacy service. <h3>Material and Methods</h3> A genetic analysis of the DPYD gene was conducted on patients who began treatment with FU (July 2023-July 2024). Variables collected included sex, age, type of mutation, prescribed drug, toxicity and dose adjustments. Data were obtained from electronic medical records and prescription program Farmis. Polymorphisms studied were c.1905+1G/A(*2A;rs3918290), c.1679T/A(*13;rs55886062), c.2846A/T(D949V;rs67376798), and c.1236G/A(HapB3;rs56038477) in the DPYD gene. Characterisation was performed by the Molecular Biochemistry service and the pharmacogenetic report was prepared by the Pharmacy service, recommending a 50% initial dose reduction with progressive adjustments based on toxicity. The percentage of acceptance by the medical team was recorded. <h3>Results</h3> 606 patients were analysed, of whom 40 (6.6%) presented with a mutated allele (52.5% male, with a median age of 64.5 (58.8–72) years). Of these, 72.5% had the c.1236G/A variant, 20% had c.2846A/T, and 7.5% had c.1905+1G/A. Of the prescribed treatments, 27.5% were 5-fluorouracil, while 47.5% were capecitabine. The rest did not receive FU-based treatment. Patients finally treated with FU (n=30) presented the following adverse effects: fatigue (50%, grade (G) 1 and 2), diarrhoea (30%, G1,2,3), peripheral neuropathy (30%, G1,2), nausea and/or vomiting (20%, G1,2), haematological toxicity (16.7%, G1,2,3), dermatological toxicity (13.3%, G1,3), aminotransferase increased (10%, G1), constipation (6.7%, G1), myalgia (6.7%, G1,2), tenesmus (6.7%, G2), and fever (3.3%, G2). Of these patients, 73.3% started with a 50% dose reduction, 3.3% with a 75% reduction, and 3.3% with an 80% reduction. Additionally, 6.7% reduced the dose after the first session due to adverse reactions. <h3>Conclusion and Relevance</h3> Despite the low incidence of these polymorphisms and the use of pharmacogenetic tools to predict potentially toxicities, patients still experience adverse effects, mainly fatigue. It is essential to investigate additional polymorphisms that may influence patient safety. This study demonstrates strong acceptance by the medical team. <h3>References and/or Acknowledgements</h3> <h3>Conflict of Interest</h3> No conflict of interest