Expanding Treatment Arsenal for Oestrogen Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

Hormonal therapy is an established treatment for oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. It is the preferred treatment due to its high efficacy and good tolerability, provided there is no immediately life-threatening visceral involvement. Aromatase inhibitors (AI) have been the standard first-line therapy for postmenopausal patients because of its superiority to older generation hormone therapies such as tamoxifen and megestrol acetate. Fulvestrant, a selective ER down regulator, has been evaluated in different dosages and combinations with other agents. Recent data suggest a greater benefit when it is used early in the disease course. A better understanding of resistance to endocrine therapy has been achieved over the past decades and new drugs have been developed to tackle alternative signalling pathways. Among them, mammalian target of rapamycin (mTOR) and cyclin-dependent kinase (CDK) 4/6 inhibitors have achieved great success in improving treatment outcome. Everolimus, an mTOR inhibitor, in combination with exemestane is effective for patients whose disease has progressed on a non-steroidal AI. CDK 4/6 inhibitors including palbociclib, ribociclib and abemaciclib have shown unique clinical efficacy and are in different phases of drug development. Their emergence has redefined the treatment strategy in both the first- and second-line settings. Today, the treatment paradigm is moving away from AI monotherapy towards hormone-targeted therapy. Research is now focused on the optimal drug combination and sequencing as well as a personalised treatment approach.