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.