Endocrine Therapy Resistance in Breast Cancer: Mechanisms and Treatments

Abstract

Breast cancers are dependent on estrogen—a hormone prevalent in females—which binds to the estrogen receptor. Estrogen drives excess proliferation of cells in which estrogen receptors are overexpressed, causing breast cancer. Estrogen receptor overexpression can be targeted by endocrine treatments, however, therapy resistance eventually develops in most cases. The four major methods of endocrine therapy are Aromatase Inhibitors (AIs), Luteinizing Hormone-Releasing Hormone Agents (LHRHs), Selective Estrogen Receptor Degraders (SERDs), and Selective Estrogen Receptor Modulators (SERMs). Treatments can be administered either adjuvantly—after primary surgery to further suppress the remaining breast cancer cells—or neoadjuvantly—prior to surgery to try and shrink the tumor. Still, resistance to these therapies occurs over 30% of the time after 2-3 years. There are multiple mechanisms that can cause resistance to endocrine therapy. These mechanisms include the upregulation of HER2 and the associated PI3K/AKT and MAPK/ERK pathways, action of the AIB1 coactivator, dysregulation of Cytochrome P450, overexpression of FOXA1 and IL-8, overexpression of NFκB, and the cyclin D/CDK4/6 complex. Two major clinical trials have been studied over the past decade for the treatment of endocrine therapy resistance, which resulted in FDA-approved interventions. These are the BOLERO-2, PALOMA-1, and PALOMA-3 trials, which have indicated that mTOR and CDK4/6 inhibitors, respectively, can reduce the resistance to endocrine therapy in ER+ breast cancer patients.