Therapies for the Treatment of Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer: Current Situation and Future Directions

Simple Summary The estrogen receptor (ER) plays a critical role in the initiation and progression of breast cancer. Utilizing specialized therapies aimed at the ER has been effective in many instances and is commonly employed in breast cancer treatment protocols. The selection of therapy depends on multiple factors, including the menopausal status, breast cancer stage, and unique tumor attributes. These therapies can function independently as monotherapy, or in conjunction or sequential alignment with other treatments, based on the distinct characteristics of the breast cancer and the patient's overall health. Furthermore, current research endeavors are focused on producing newer and more precise therapies for breast cancer, which include strategies to combat resistance mechanisms. The objective of this review is to provide a snapshot of the existing landscape and sketch out future paths for the progression of HR+ breast cancer treatments currently under clinical development.Abstract The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ER alpha. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development.