Feasibility of DPYD Genotyping in Australian Cancer Patients

Abstract

Abstract Background. Fluoropyrimidine (FP) chemotherapies are widely prescribed for solid organ malignancies, including colorectal, gastrointestinal, breast and head and neck cancers. They are prescribed for over 10,000 Australian cancer patients per year. Between 10-40% of patients experience serious (grade 3-5) toxicities that can result in hospitalisation, intensive care admission and even death. Dihydropyrimidine dehydrogenase (DPD) is the critical enzyme involved in FP metabolism and accounts for a significant proportion of FP toxicities. Measuring DPD is difficult and alternate measures include DPYD (encoding DPD) genotyping to determine clinically significant variants. FP dosing for DPYD genotype carriers can be adjusted according to international guidelines to reduce FP toxicities and improve patient tolerance. Methods. We determined the turnaround time (TAT) for genotyping 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/Haplotype B3) in an Australian patient cohort, utilising a public health care service testing facility. We identified toxicities of DPYD variant carriers. Health care stakeholder perspectives were explored by survey, including perceived enablers and barriers to implementation and their solutions. Results. 104 patients were recruited. One patient declined testing after enrolment. With one genotyping run per week, mean TAT was 7.2 days (range 1-30). Sixteen patients were found to have DPYD variants. G3-5 toxicity occurred in 10/16 variant carriers, including 2 ICU admissions and 1 death. Thirty surveys were received from stakeholders with common themes being the environment and resources being the fundamental barriers and motivation to improve patient care a predominant enabler of change. Conclusions. DPYDgenotyping is a feasible pharmacogenomic (PGx) screening test within the public healthcare system for patients intending to receive FP chemotherapies. This TAT is comparable to international standards and allows adequate time for clinical decision-making and DPYD genotype-guided FP dose adjustment. Perceived barriers and enablers were predictable and will help to assist strategic support for larger scale implementation. Further information is required to determine population frequency and toxicities of variant carriers following dose adjustment in the Australian population. Trial Registration: ACTRN12622000963729, retrospectively registered 07/07/2022