Prophylactic dihydropyrimidine dehydrogenase (DPYD), and reactive cytidine deaminase (CDA) testing is feasible and reduces severe toxicity in Irish patients receiving 5-fluorouracil (5-FU) based chemotherapy.

Abstract

3600 Background: 5-Fluorouracil (5-FU) steady state concentrations can vary up to fourfold among cancer patients. 5-FU intolerance and toxicity is associated with reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD) due to polymorphisms of the DPYD gene, as well as mutations in cytidine deaminase (CDA). Since 2012, Bon Secours Hospital, Cork has implemented prophylactic DPYD screening to reduce toxicity. Methods: In this retrospective cohort study, 742 adult cancer patients who underwent reactive or prophylactic DPYD testing in our center between 2012 and 2019 were included. Reactively tested patients were screened prior to 2012. 5-FU related toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and analysed. Frequencies of polymorphisms in DPYD, affecting 5-FU metabolism in patients who experienced severe toxicity are described, in both patients who were retrospectively tested, and in our larger prophylactic patient cohort. Mutations of genes encoding CDA were also analysed. Analysis of type and severity of toxicity, and survival analysis will be presented at the Annual Meeting. Results: 742 patients were tested for DYPD in our centre, of which 704 were prophylactic tests. 11.4% of the patients tested prophylactically were found to have polymorphisms in the DYPD gene. Expectedly, a higher proportion of patients tested reactively were found to have polymorphisms in DYPD (21.9%). 21 out of 34 patients who had severe toxicity had CDA mutations present on testing. Further data involving classification and severity of toxicities, along with survival analysis will be presented at the Annual Meeting. Conclusions: The prevalence of DPYD mutations in Ireland is estimated to be 7-10%, and is putatively responsible for approximately 20% of all severe 5-FU toxicities suffered by cancer patients. Implementing prophylactic DPYD screening is beneficial in reducing toxicities in this setting. Future work will focus on phenotypic measurements of uracil metabolism and pharmacokinetic 5-FU monitoring to further reduce toxicity in patients who do not have DPYD mutations.