The Value of Pharmacogenetics to Reduce Drug-Related Toxicity in Cancer Patients

Many anticancer drugs cause adverse drug reactions (ADRs) that negatively impact safety and reduce quality of life. The typical narrow therapeutic range and exposure-response relationships described for anticancer drugs make precision dosing critical to ensure safe and effective drug exposure. Germline mutations in pharmacogenes contribute to inter-patient variability in pharmacokinetics and pharmacodynamics of anticancer drugs. Patients carrying reduced-activity or loss-of-function alleles are at increased risk for ADRs. Pretreatment genotyping offers a proactive approach to identify these high-risk patients, administer an individualized dose, and minimize the risk of ADRs. In the field of oncology, the most well-studied gene-drug pairs for which pharmacogenetic dosing recommendations have been published to improve safety are DPYD-fluoropyrimidines, TPMT/NUDT15-thiopurines, and UGT1A1-irinotecan. Despite the presence of these guidelines, the scientific evidence showing the benefits of pharmacogenetic testing (e.g., improved safety and cost-effectiveness) and the development of efficient multi-gene genotyping panels, routine pretreatment testing for these gene-drug pairs has not been implemented widely in the clinic. Important considerations required for widespread clinical implementation include pharmacogenetic education of physicians, availability or allocation of institutional resources to build an efficient clinical infrastructure, international standardization of guidelines, uniform adoption of guidelines by regulatory agencies leading to genotyping requirements in drug labels, and development of cohesive reimbursement policies for pretreatment genotyping. Without clinical implementation, the potential of pharmacogenetics to improve patient safety remains unfulfilled.