Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers

Abstract

Purpose: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer.

Methods: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes.

Results: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme.

Conclusion: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

FIG 1.

Subject-level prevalence for composite precision medicine opportunities, including actionable PGx, management of serious CYP-mediated DDIs, and management of DDIs including acid reducers and TKIs. CYP, cytochrome P450; DDI, drug-drug interaction; PGx, pharmacogenetics; TKI, tyrosine kinase inihibitors.

FIG 2.

Subject-level prevalence of clinically actionable phenotypes for major CYP enzymes on the basis of genotype and because of CYP inhibitor–mediated phenoconversion. CYP, cytochrome P450.