Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2- Breast Cancer

Approximately 70–80% of breast cancers are ER+ and 65% of them also are ER+PR+. In most cases of ER+ advanced disease, endocrine therapy (ET) is the initial treatment with different drugs that act by inhibiting the ER signaling, mainly tamoxifen, a selective estrogen receptor modulator (SERM), or fulvestrant, a selective estrogen receptor degrader (SERD), or by impeding the estrogen formation as aromatase inhibitors (AIs). However, hormone resistance intrinsic or acquired, eventually develops, making disease progression unavoidable. An increased progression-free survival (PFS) and, sometimes, overall survival (OS) recently occurred after the association of ET with the cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6is) that block cell-division cycle in the G1 phase and halt DNA production thus synergizing with ET. This review focuses on the main mechanisms of resistance to ET, whether used alone or in combination with biological agents, and on new drugs/strategies currently in use or under investigation to overcome it. Overcoming resistance to ET is a “work in progress” and early in the next it is expected to better select patients for different therapeutic strategies based on more specific biologic and/or genetic markers. Particularly, liquid biopsy may provide a real-time portrait of the disease state including mechanisms responsible for ET independence and cancer proliferation.