Pharmacogenomics: DPYD and Prevention of Toxicity

In 2020, the introduction of pre-emptive DPYD genotyping prior to the administration of systemic fluoropyrimidine-based chemotherapy represented one of the first widespread pharmacogenetic testing programmes to be applied nationally in the United Kingdom. Pharmacogenetic variants in the DPYD gene found in between 3 and 6% of the population are a recognised cause of primary DPD enzyme deficiency and associated increased risk of severe fluoropyrimidine toxicity [1]. Yet, the availability of testing globally is heterogeneous. Despite growing evidence that in addition to reducing drug-induced toxicity, DPYD-guided dosing does not negatively affect outcomes, further research on the impact of routine DPYD genotyping in the UK population is required. With mandatory testing in the UK focussed on four well-characterised variants, there is a need to address the applicability of this strategy across diverse ethnic or ancestral populations. We highlight approaches to identify and characterise rare variants in DPYD and in other genes involved in the pyrimidine metabolic pathway to reduce healthcare inequalities. Finally, we discuss the future of pharmacogenomics within cancer care, and the potential to harness innovative digital and genotyping technologies to streamline prescribing and optimise both systemic anti-cancer therapies and supportive care.