Potential Utility of Pre-Emptive Germline Pharmacogenetics in Breast Cancer.

Philip S Bernard,Gwendolyn A Mcmillin,Mei Wei,Steven M Bray,Kevin C Wood,Whitney Wooderchak-Donahue,Baiju Parikh

doi:10.3390/cancers13061219

Abstract

Simple SummaryBreast cancer outcomes are variable due to differences in tumor biology, patient biology, and treatment. The likelihood of developing cancer and other diseases increases with age. Thus, many patients with breast cancer have multiple co-morbidities requiring medical management, which increases the probability of polypharmacy and the risk of adverse drug events. Pharmacogenetics is the study of how inherited genetic variants influence drug response. Depending on the genes that a patient inherits, some respond to drugs as expected, some experience debilitating side effects, and others have minimal to no response. In this paper, we discuss the theoretical clinical utility of pharmacogenetics for 225 patients with breast cancer relative to anti-cancer drugs and non-cancer drugs. For this population, 38 drug–gene associations with high levels of evidence for clinical actionability were identified, supporting the concept of pharmacogenetics integration into the routine care of future patients with breast cancer. Patients with breast cancer often receive many drugs to manage the cancer, side effects associated with cancer treatment, and co-morbidities (i.e., polypharmacy). Drug–drug and drug–gene interactions contribute to the risk of adverse events (AEs), which could lead to non-adherence and reduced efficacy. Here we investigated several well-characterized inherited (germline) pharmacogenetic (PGx) targets in 225 patients with breast cancer. All relevant clinical, pharmaceutical, and PGx diplotype data were aggregated into a single unifying informatics platform to enable an exploratory analysis of the cohort and to evaluate pharmacy ordering patterns. Of the drugs recorded, there were 38 for which high levels of evidence for clinical actionability with PGx was available from the US FDA and/or the Clinical Pharmacogenetics Implementation Consortium (CPIC). These data were associated with 10 pharmacogenes: DPYD, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, G6PD, MT-RNR1, SLCO1B1, and VKORC1. All patients were taking at least one of the 38 drugs and had inherited at least one actionable PGx variant that would have informed prescribing decisions if this information had been available pre-emptively. The non-cancer drugs with PGx implications that were common (prescribed to at least one-third of patients) included anti-depressants, anti-infectives, non-steroidal anti-inflammatory drugs, opioids, and proton pump inhibitors. Based on these results, we conclude that pre-emptive PGx testing may benefit patients with breast cancer by informing drug and dose selection to maximize efficacy and minimize AEs.

Highlights

Breast cancer outcomes are variable due to differences in tumor biology [1,2], patient biology [3,4], and treatment availability [5,6]
Some combinations of drugs have potential to interact with one another, which can contribute to adverse events (AEs) [11]
Inherited variations in the genes involved in drug response may independently impact drug response and/or may exacerbate drug–drug interactions [12]

Summary

Introduction

Breast cancer outcomes are variable due to differences in tumor biology [1,2], patient biology [3,4], and treatment availability [5,6]. In addition to anti-cancer treatment, cancer patients often receive medications for co-morbidities and supportive care [7], resulting in polypharmacy and an increased likelihood of adverse events (AEs), therapeutic failure, non-standard dose requirements, and/or non-adherence [8,9]. Some combinations of drugs have potential to interact with one another (drug–drug interactions), which can contribute to AEs [11]. Inherited (germline) variations in the genes involved in drug response may independently impact drug response (drug–gene interactions) and/or may exacerbate drug–drug interactions [12]. “Pharmacogenetics” (PGx) and “pharmacogenomics” refer to germline variants in genes that are involved in drug response. PGx generally describes single gene–drug associations, whereas pharmacogenomics considers the impact of many genes, as in the genome

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