A Pharmacogenomic Basis for Tolerance of 5-Fluorouracil Following Early, Severe Toxicity from Capecitabine in a CDA Ultrarapid Metabolizer Colon Cancer Patient: A Case Report

Tinashe Adrian Mazhindu,1,2 Zedias Chikwambi,1 Edith Matsikidze,2 Kevin V Grimes,3 Margaret Z Borok,4 Ntokozo Ndlovu,1,2 Collen Masimirembwa1 On behalf of Consortium for Genomics and Therapeutics in Africa1Department of Clinical Research and Services, African Institute of Biomedical Sciences & Technology, Harare, Zimbabwe; 2Department of Oncology, Medical Physics and Imaging Science, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe; 3Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA; 4Department of Internal Medicine, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, ZimbabweCorrespondence: Tinashe Adrian Mazhindu, Email [email protected]: Capecitabine is an oral prodrug that is converted to 5-FU via three enzyme-catalysed steps: carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TYMS). Approximately 80– 90% of 5-FU, whether from capecitabine or direct administration, is quickly inactivated by dihydropyrimidine dehydrogenase (DPD), encoded by DPYD. Preemptive testing for four pathogenic DPYD variants that reduce DPD activity is advised; however, currently, no evidence for CES, CDA, or TYMS has necessitated a similar recommendation despite polymorphisms in these genes potentially causing treatment toxicity. The current preemptive testing guidelines for 5-FU and capecitabine are similar.Case Presentation: A 74-year-old black woman with a caecal adenocarcinoma diagnosis of pT4bG1N0M0 was prescribed adjuvant oxaliplatin and capecitabine post-hemicolectomy. On day 16 of the first cycle, she presented with severe gastrointestinal, myelosuppressive, hand and foot side effects and enterocolitis infection. She underwent a pharmacogenomic workup with whole-exome sequencing and was noted to be genetically DPD non-deficient (DPYD *1/*9A). She was found to express CDA rs3215400 (c.-33delC) and CDA rs1048977, both of which are associated with an increased risk of toxicity from capecitabine. CDA rs3215400 has been specifically described as an ultrametabolizer variant with an observation to increase enzyme activity by 3– 7 fold and the occurrence of adverse drug events in capecitabine. After recovery and follow-up, she continued to receive 5-FU, leucovorin, and oxaliplatin therapy which she tolerated well and completed six months of therapy.Conclusion: This case shows that the severe adverse effects of capecitabine therapy in a patient with a CDA ultrametabolizer profile can be successfully switched to 5-FU-based therapy at a normal dose and tolerate this alternative fluoropyrimidine.Keywords: fluoropyrimidine, genetic polymorphisms, toxicity, precision medicine, gastrointestinal cancer