Management of hormone-receptor positive human epidermal receptor 2 negative advanced or metastatic breast cancers

Hormone therapy, rather than chemotherapy, is recommended for hormone-receptor positive (HR+), human epidermal receptor 2 negative (HER2−) advanced or metastatic breast cancer (A/MBC) according to the European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines, unless in visceral crisis in which chemotherapy is indicated. Hormonal monotherapy of selective estrogen receptor modulator (SERM) or selective estrogen receptor down-regulator (SERD), aromatase inhibitor (AI), or their combination as doublets, used to be the mainstay options as first-line (1L) therapy for most patients. More recently, combination targeted drugs plus AI or SERD (such as fulvestrant) has been extensively investigated in both 1L and second-line (2L) treatments of HR+ HER2− patients. Cyclin-D kinase 4/6 inhibitors (CDK4/6i) can halt tumor proliferation by blocking the ER related transcription signaling that drives the CDK4/6-dependent cell cycle in HR+ tumors, and they work best together with AI or SERD. On the other hand, favorable results were reported from inhibition of m-TOR pathway, both in 2L setting when PI3K-AKT-mTOR pathway is frequently overexpressed, as well as in 1L setting. Currently, the major guidelines have all included CDK4/6i plus AI as a standard 1L therapy, while Everolimus plus AI, and CDK4/6i plus fulvestrant, are recommended 2L options. Selecting appropriate patients for such therapeutic options and harnessing the sequence of these new therapies in the new paradigm of managing HR+ HER2− A/MBC are the key priorities for future clinical research.