Personalizing aromatase inhibitor therapy in patients with breast cancer

BACKGROUND:Aromatase inhibitors are the mainstay of therapy for patients with hormone receptor-positive breast cancer in both adjuvant and metastatic settings. Their use in clinical practice has been challenged by significant inter-individual variability in response and tolerability. Hence, the purpose of this paper is to provide a succinct review of the literature on the genetic factors contributing to this variability. DESIGN:A systematic search in PUBMED was conducted to identify studies that investigated the association between germline polymorphisms and disposition, clinical response and toxicities of aromatase inhibitors, as well as those evaluating the implications of mutations in ESR1 on clinical response. RESULTS:Polymorphisms in genes coding for phase I and phase II enzymes (pharmacokinetic genes) significantly modulated exposure to aromatase inhibitors; however, there is a paucity of data linking interindividual variability in drug exposure to clinical response. Furthermore, pharmacogenetic studies interrogating relationship between polymorphisms in CYP19A1 (the target site of aromatase inhibitors, i.e. a pharmacodynamic gene) and response yielded conflicting results. Acquired mutations in ESR1 receptors have been identified as the underlying mechanism of resistance to aromatase inhibitors, and likely predict drug response. Although some pharmacogenetic studies have implicated polymorphisms in CYP19A1 and ESR1 with drug-related side effects, the putative role of these genes in predicting toxicity warrants further validation. CONCLUSION:Genetic polymorphisms in pharmacokinetic and pharmacodynamic genes appear to influence aromatase inhibitor disposition, response and/or toxicity; however, prospective interventional studies are needed to understand the application of genomics to personalize aromatase inhibitor therapy in breast cancer patients.