Metastatic breast cancer: Endocrine therapy landscape reshaped

Abstract

Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus. Although still considered incurable by currently available treatment modalities, many patients with MBC nowadays enjoy several years of good quality life coupled with decent tumor control. The diversity of therapies and unusual pattern of side effects can be quite perplexing to the treating physician. The sequence of variable agents and management of side effects, in addition to the timing of initiation of cytotoxic chemotherapy, is among the challenges faced by oncologists. In this review, we shed a spotlight on mechanisms of resistance to ET, and provide a review of landmark studies that have recently reshaped the landscape of treatment options for patients with metastatic HR-positive, HER2-negative MBC. A suggested treatment strategy for newly diagnosed patients is also discussed herein.

Keywords: Breast cancer; endocrine therapy; metastatic.

Figure 1

A suggested treatment algorithm for newly diagnosed MBC patients. a: Switching to endocrine therapy after a period of chemotherapy may be considered in this scenario. b: In patients who previously received exemestane in the metastatic settings or within 12 months before relapse, consider other endocrine therapy combinations with everolimus such as either fulvestrant or tamoxifen. c: Consider this combination option, especially in everolimus-naïve patients who previously received exemestane. d: There is insufficient evidence to support the continued use of CDK4/6 inhibitors in patients who progressed while taking an agent from the same class. *Clinical trial participation is encouraged in the first line of therapy or at the time of progression, whenever feasible. MBC: Metastatic breast cancer, AI: Aromatase inhibitor, GnRH: Gonadotropin-releasing hormone, BSO: Bilateral salpingo-oophorectomy, CDK: Cyclin-dependent kinase