Emerging mechanisms of therapy resistance in metastatic ER+ breast cancer

Breast cancer is the most frequently diagnosed cancer in women with over 316,000 new cases expected to be diagnosed in 2025. Nearly 80% of new breast cancer cases will be estrogen receptor-positive (ER+). While ER+ breast cancer has a high 5-year survival rate, patients are at risk of developing late recurrence and metastasis for 10 to 20 years after initial diagnosis. Late recurrence and metastasis are associated with therapy resistance and disease progression. Understanding the molecular mechanisms that drive therapy resistance and disease progression is essential for the development of therapies that will prevent and treat advanced ER+ breast cancer. This review will focus on mechanisms of therapy resistance associated with standard treatments for advanced ER+ breast cancer, including CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR pathway inhibitors. Additionally, we will highlight how therapy resistance enriches for breast cancer stem-like populations and how targeting this population of cells may be advantageous for preventing breast cancer progression.