Implementing DPYD genotyping to predict chemotherapy toxicity in Australia: a feasibility study.

Background: Implementing pharmacogenomic-guided management in cancer patients equitably and effectively in a large population presents challenges. DPYD genotyping determines clinically significant variants of patients at increased risk of developing grade3-5 fluoropyrimidine (FP) toxicity. FP chemotherapies are prescribed for ~16,000 Australians with a 10%-40% grade3-4 toxicity incidence and 1% mortality. Variant carriers can have FP dosing adjusted to improve treatment tolerance without compromising anticancer effect. This strategy has not been formally adopted within Australia, despite widespread international standardisation.

Aim: This pilot study determined genotyping turnaround-times (TAT) for 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/Haplotype B3) in Australian patients. Secondary objectives were identification of FP toxicities of DPYD variant carriers, and analysis of healthcare stakeholder perspectives, including enablers/barriers to implementation.

Methods: Genotyping was determined by Real-Time Polymerase Chain Reaction. Qualitative data were determined through semi-structured questionnaire.

Results: 104 patients recruited over 24 months had a mean TAT of 7.2 days, 5.2 business days (range 1-30). Grade3-4 toxicity occurred in 9/16 DPYD variant carriers, including 2 ICU admissions and 1 death. Themes from 30 questionnaire respondents suggest that clinical environment and resources were fundamental barriers, and motivation to improve patient care was the predominant enabler of change.

Conclusion: DPYD genotyping is feasible for improving precision-oncology for patients requiring FP chemotherapies. A TAT of 7 days is acceptable by both stakeholder respondents and national oncology clinician groups. This pilot study, although small, informs a large national project evaluating prospective DPYD genotyping and its impact on FP tolerability, patient safety and cost-effectiveness in Australia.