Deaths from metastatic breast cancer continue to be a leading cause of global cancer mortality among women. The pace of advances in the treatment of hormone-receptor positive metastatic breast cancer (HR+ MBC) has introduced nuance and complexity in choosing between available agents as patients and physicians explore options across lines of therapy. In this review, we explore the modern paradigm of treatment options and the sequential approach to HR+ MBC, as well as treatment options on the horizon, and the particular impact on survival outcomes and the associated adverse effects of those treatments. We discuss the diagnostic approach, first- and second-line management, as well as management of later-line endocrine-refractory HR+ MBC. Treatments discussed include cyclin-dependent kinase 4/6 inhibitors, antibody drug conjugates, and targeted therapies against phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit alpha (PIK3CA), estrogen receptor 1 (ESR1), and poly[ADP-ribose] polymerase (PARP), among others. Building from the initial diagnostic approach, we describe how to pragmatically layer options by appropriate line of therapy and personalized drivers of disease to aid in treatment decision making stepby-step. Combining sequential treatment options, evolving treatment options, and advanced genetic and genomic testing along with shared decision making between patients and physicians, this review aims to outline the key factors that ultimately drive the decisions for treatment in hormone-positive metastatic breast cancer.
