The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors

ABSTRACT

Introduction: Breast cancer is the most common female cancer and remains a serious public health concern worldwide. Third-generation aromatase inhibitors (AIs) are widely used in postmenopausal women with estrogen receptor positive breast cancer. However, there is marked interindividual variability in terms of the efficacy and incidence of adverse events following treatment with AIs. Pharmacogenetics has the potential to predict clinical outcomes based on patients’ genetic information, paving the way towards personalized treatment.

Areas covered: This article reviews pharmacogenetic studies of AIs, including pharmacokinetic and pharmacodynamic aspects, highlighting those studies where the efficacy and adverse events of AIs have been examined using both candidate gene and genome-wide approaches.

Expert opinion: Pharmacogenetics is a promising approach to develop personalized medicine with AIs. However, the application of pharmacogenetics to predict therapeutic efficacy and adverse events in breast cancer patients is still far from implementation in routine clinical practice. Large, comprehensive, multicenter studies that simultaneously evaluate multiple genes and pathways, including rare variants, are warranted in order to produce reliable and informative results. The ultimate aim is to develop clinically-relevant guidelines for breast cancer therapy.

KEYWORDS:

• Aromatase inhibitors
• pharmacogenetics
• pharmacokinetics
• pharmacodynamics

Article highlights

• Breast cancer is the most frequent female cancer and the leading cause of cancer-related deaths in women worldwide.

• Clinical outcome following treatment with AIs is highly variable, and patients experience variation in clinical tolerance. Therefore, there is an urgent clinical need to identify biomarkers for predicting therapeutic efficacy and adverse events of AIs.

• CYP2A6 genetic variation could explain 23% of the variability in plasma letrozole concentration.

• As an important tool for pharmacogenetic researches, genome-wide association study identified novel SNPs that are close to the TCL1A gene to be associated with MS-AEs. However, a subsequent study was unable to validate these findings.

• Large, multicenter studies are required to simultaneously evaluate multiple genes and pathways, including rare variants.

• Subsequent verification through replication studies and prospective trials should be conducted to evaluate the benefit of pharmacogenetic testing in the clinical setting and to produce reliable and informative results, aiming at practical clinical applications for breast cancer therapy.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.