ER plus metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future

The importance and role of the estrogen receptor (ER) pathway have been well-recognized in both breast cancer development and progression. The treatment of choice in women with estrogen receptor-positive metastatic breast cancer (ER+ mBC) is classically divided into a variety of endocrine therapies, with three of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (Al), and selective estrogen receptor degraders (SERD). However, resistance develops in 30-50% of patients treated with these endocrine therapies due to a sophisticated and at times redundant interference at the molecular level between the ER, growth factors, and downstream cell-signaling pathways. Tumor response is heightened with adjunctive therapy that includes an mTORC1 inhibitor (everolimus), CDK4/6 inhibitors (palbociclib/ribociclib/abemaciclib), and an a isoform-specific P13K inhibitor (alpelisib). Each of these inhibitors elicits potent anti-proliferative benefits; however, they fail to induce tumor cell death. Consequently, disease progression almost invariably occurs. Evasion of apoptosis is a hallmark of cancer. The p53 and BCL2 represent two important nodes of the apoptosis signaling pathway. Venetoclax, a potent and selective BCL2 inhibitor, synergizes with hormonal therapy in ER+ breast cancer models and is active in clinical trials. Similarly, an MDM2 inhibitor, AMG-232, which induces p53 is active in early clinical trials of both liquid and advanced solid tumor patients. In our ER+ BC cohort (Avera Cancer Institute, Sioux Falls, SD), we observed more than 70% of wild type TP53 and over 10% amplification of MDM2 and MDM4 as comparable with the TCGA data set. We summarized current treatment options, the molecular mechanisms that predispose to endocrine resistance, and a future pro-apoptotic treatment strategy for ER+ mBC patients. Our review presents critical analyses of the therapeutic options for the clinical management of ER+ Metastatic Breast Cancer in the light of a hypothesis targeting the induction of apoptosis in p53 wild type tumors. We reviewed not only the FDA approved current treatment approaches but also presented a discourse addressing the possibilities for novel combination strategy that can induce tumor cell apoptosis, a critical cellular mechanism delaying/denyingtumor progression. Our review is unique as it presents patient data in support of our hypothesis.