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CLINICAL OPPORTUNITIES FOR GERMLINE PHARMACOGENETICS AND MANAGEMENT OF DRUG-DRUG INTERACTIONS IN PATIENTS WITH ADVANCED SOLID CANCERS

By Tyler Shugg, Reynold C Ly, Elizabeth J Rowe, Santosh Philips, Mustafa A Hyder, Milan Radovich, Marc B Rosenman, Victoria M Pratt, John T Callaghan, Zeruesenay Desta, Bryan P Schneider, Todd C Skaar

Posted 30 Aug 2021
medRxiv DOI: 10.1101/2021.08.23.21262496

PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit advanced cancer patients 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. PATIENTS AND METHODS: Medication data were collected from the electronic health records (EHRs) for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium (CPIC) 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 CPIC recommendations, and ~14% of subjects had an instance for actionable PGx, defined as prescription of 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, ~40% of subjects had at least one opportunity for a precision medicine-based intervention and ~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.

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