Pharmacogenetics and pharmacogenomics of endocrine agents for breast cancer

The clinician caring for women with early breast cancer is keenly aware of the variability observed when endocrine therapy with tamoxifen or the aromatase inhibitors (AIs) is employed. This is seen in outcomes of the disease in terms of recurrence but also, strikingly in some cases, in terms of adverse events. This can be seen in the case of AIs, in which some women develop disabling musculoskeletal events that result in their discontinuing therapy, whereas the majority develops no such adverse events. The same is true of other adverse events such as deep venous thrombosis, endometrial cancer and hot flashes in the case of tamoxifen. In the past, the focus in selection of therapy for women with breast cancer has been almost exclusively on the characteristics of the tumour (for example, oestrogen receptor [ER] and human epidermal growth factor receptor [HER]-2), with essentially no attention given to the genetic make-up of the patient. Pharmacogenetics and pharmacogenomics involve the study of the role played by inheritance in individual variation in drug response phenotypes such as disease outcomes and end organ effects, including adverse events. These terms are often used interchangeably but, strictly speaking, pharmacogenetics refers to the study of a gene or a number of genes, such as those involved with a pathway, whereas pharmacogenomics involves the entire genome. We have truly entered the era of pharmacogenomics with the introduction of genome-wide association studies (GWASs). Pharmacogenetics/pharmacogenomics have the clinical goals of better selecting responsive patients, maximizing drug efficacy and minimizing adverse reactions. Pharmacokinetics considers factors such as metabolism and transport that influence drug concentrations at the target(s), whereas pharmacodynamics considers factors that influence the response of the target(s), for example receptors, enzymes, transporters and downstream signalling molecules, to the drug. Endocrine therapy represents the most important therapeutic modality for those women whose tumours are potentially endocrine sensitive, as indicated by expression of the ER and/or progesterone receptor. The selective ER modulator tamoxifen has been the most important therapeutic agent in breast cancer for the past three decades. Tamoxifen has received approval from the US Food and Drug Administration for the full spectrum of breast cancer from metastatic disease to those women who are at higher risk for developing breast cancer. In addition, tamoxifen has received approval for treatment of men with metastatic breast cancer and is commonly used in the adjuvant setting. During the past decade the third generation AIs anastrozole, exemestane and letrozole have emerged as important additions to the clinician's armamentarium against breast cancer. They appear to be more efficacious than tamoxifen in the advanced disease setting [1], have become clearly established in the adjuvant setting [2] and are a major focus of ongoing trials in the prevention setting in postmenopausal women [3]. Tamoxifen and the AIs have recently become foci of intense pharmacogenetic/pharmacogenomic research [4].