Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA
Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.
Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1
A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13
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