The last decade has brought substantial improvements to all types of systemic therapy for breast cancer. Thus, hormonal therapy has been improved by development of the novel, third-generation aromatase inhibitors, initially in the metastatic, subsequently followed by successful implementation in the adjuvant setting. For chemotherapy several novel compounds, including vinorelbine and navelbine have been introduced, with the most substantial improvements achieved through implementation of the taxanes. Finally, targeted therapy took a major step forward through the exiting preliminary results obtained with trastuzumab in the adjuvant setting.

Despite improvement in therapy, metastatic breast cancer remains a non-curable condition. Taking the group in total, median survival remains in the range of 2-2.5 years (1, 2). Notably, however, life expectations vary significantly between different subgroups. While life expectancy from time of diagnosis of distant metastases depends on issues like tumor burden, it is even more related to tumor-"intrinsic" biology. Thus, it has been known for decades that estrogen receptor (ER) positive tumors in general has a slower growth rate compared to the estrogen receptor negative ones. This is manifested by the fact that ER positive tumors in general relapse later (more than 2 years after primary diagnosis) in comparison to the ER negative ones (3), but even more to the fact that average life expectancy from time of distant metastases appearing is longer (4, 5). ER positive disease in general is frequently associated with locoregional relapse but, in particular, distant metastases affecting the skeletal system, contrasting the predilection of ER negative disease for visceral organs (6, 7). Thus, many patients expressing skeletal metastases may live with their disease for several years. However, it should be underlined that for patients with distant metastases the long-term prognosis is as serious for ER positive as it is for ER negative disease (4).

The fact that metastatic breast cancer remains noncurable and therapy palliative, underlines the importance of limiting toxicity of therapy. Endocrine therapy in general provides limited toxicity in comparison to chemotherapy; thus, hormonal manipulation remains no only first-line therapy but should be extended as far as possible for patients with endocrine-sensitive advanced disease. For this reason, we will provide a brief description of the different treatment options and their mechanisms of action (Fig. 1). We will include treatment options no longer in general use, as they may be of value in late sequential treatment for the subgroup of patients whose tumors may respond to multiple endocrine treatment strategies. Importantly, although most patients with initially hormone-sensitive tumors will develop acquired resistance following two or perhaps three different regimens, some patients may respond to multiple different treatments options (like additive therapies with estrogens at high doses) administered sequentially (8). Accordingly, such patients may achieve disease control for years on different endocrine regimens with no need for chemotherapy. While previous endocrine treatment options, like additive treatment with estrogens or progestins administered in pharmacological doses have been abandoned in favor of contemporary treatment options for safety reasons, notably, the discomfort associated with such therapy is moderate compared to what most patients experience on chemotherapy.

Figure 1. Endocrine treatment options for metastatic breast cancer.
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