Management of ER positive metastatic breast cancer.

There are over 2 million cases a year of breast cancer, leading to over 600,000 deaths globally [1]. Despite these large numbers, increasingly more women are being cured with early stage disease and women with advanced disease are living longer [2]. The appreciation for molecular subtypes of the disease has led to significant therapeutic advances and estrogen receptor positive (ER+) breast cancer represents the largest of these subgroups. An appreciation for the importance of estrogen signaling in ER+ dates back to 1896 when Dr. George Thomas Beatson observed impressive disease responses after performing bilateral oophorectomy in 3 women at Glasgow Cancer Hospital [3]. The evolution of treatment for advanced disease from progestins, to the selective estrogen receptor modulator tamoxifen, and subsequently the aromatase inhibitors and the selective estrogen receptor degrader fulvestrant, has been accompanied by improved efficacy and decreased side effects. While the use of these drugs has changed the natural history of both early and advanced disease, it has been long recognized that many patients will develop resistance to this approach. After many years of trying to improve on single-agent endocrine treatment, since 2012 there has been an explosion of new drugs that have shown improved efficacy in combination with endocrine approaches. The first of these to receive FDA approval was the mTOR inhibitor everolimus (2012) [4], followed by the approval of 3 cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors [palbociclib (2015) [5], ribociclib (2018) [6], and abemaciclib (2018) [7]], and more recently the PI3-kinase inhibitor alpelisib (2019) [8]. In addition, chemotherapy is still used frequently when endocrine manipulations have been exhausted. Like other incurable malignancies, the goal in advanced ER+ breast cancer is to prolong survival and maintain quality of life. Currently, we have more tools available to achieve this than ever before and we will review the efficacy and side effect data with these agents that are driving physician choices for individual patients.