Postoperative endocrine therapy for invasive breast cancer.

Estrogen plays a key role in mammary carcinogenesis, identifying the pathways that regulate estrogen function as major targets for breast cancer therapy. Expression of the estrogen receptor α (ERα) or the progesterone receptor (PR) is a widely recognized predictor of response to hormonal therapy [1]. Studies of endocrine manipulation conducted in advanced breast cancer have revealed response rates of 80% for ER+/PR+ tumors, 40–45% for ER−/PR+ tumors, 25–30% for ER+/PR− tumors, and less than 10% for ER−/PR− tumors. More recently, data have demonstrated that over-expression of ER or PR in at least 1% of breast tumor cells indicates potential responsiveness to endocrine therapy [2, 3]. In the absence of ER or PR expression, endocrine therapy is not indicated. These observations highlight the importance of an accurate measurement of ER and PR expression in the primary tumor in therapeutic decision-making. Currently, quality-controlled quantitative immunohistochemistry is the method of choice [4, 5]. The estrogen pathway can be manipulated by several distinct strategies. Estrogen production itself can be decreased by ovarian ablation/suppression [6] or aromatase inhibitors [7]. Alternatively, ERα activity can be modulated using Tamoxifen or other selective estrogen receptor modulators (SERMs) like Raloxifene [8]. Furthermore, the ERα can be downregulated by Fulvestrant, a selective estrogen receptor destroyer (SERD) [9]. Ovarian function has a major impact on circulating levels of estrogen, and menopausal status drives decision-making when choosing endocrine therapies for women with invasive breast cancer. In premenopausal women, the ovary is the major source of estrogen production. A smaller amount of estrogen is produced by extragonadal aromatase, which catalyzes the conversion of androstenedione and testosterone to estrone and estradiol respectively. In postmenopausal women, peripheral aromatization is the primary source of estrogen. Therefore, ablating ovarian function by surgical removal, targeted medical suppression, or the indirect effects of chemotherapy is most effective for decreasing estrogen levels in women with intact ovarian function. In contrast, the prevention of extragonadal estrogen production by inhibiting aromatase is the most effective means of decreasing estrogen levels in postmenopausal women. Importantly, the most recent Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview analysis demonstrated that 5 years of adjuvant Tamoxifen reduced the annual rate of death by 31% among women with ER+ breast cancer, regardless of age [10]. However, recent advances in breast cancer biology have highlighted the heterogeneity of the disease, with gene expression profiles classifying luminal A and luminal B as two distinct biological subtypes of ER+ breast cancer with very different natural histories [11–13]. Further, multiple mechanisms of resistance to endocrine therapy can account for Tamoxifen failure. These include de novo resistance pre-determined by tumor cell biology [14], acquired resistance that develops over time with treatment [15], genetic resistance related to inherited differences in drug metabolism [16], or unresponsive estrogen/progesterone receptor variants [17]. These findings, together with both the emergence of new drugs and the resurgence of old therapies, highlight the complexity of treatment decision-making for women with ER+ disease. Here, we present an overview of the current data guiding the use of endocrine manipulation for early breast cancer treatment, and highlight emerging opportunities for further refinement.