Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer

Anti-oestrogen-based therapies, often combined with a CDK4/6 inhibitor, are the current standard-of-care first-line therapy for patients with advanced-stage hormone receptor-positive (HR + ) breast cancer. Resistance to anti-oestrogen agents inevitably occurs, mediated by oestrogen receptor (ER)-dependent or ER-independent mechanisms that drive tumour progression. Emerging endocrine therapies include, but are not limited to, next-generation oral ER degraders and proteolysis targeting chimeras, which might be particularly effective in patients with ESR1 -mutant breast cancer. Furthermore, cancers harbouring driver alterations in oncogenic signalling pathways, including AKT and PI3K, might be susceptible to novel combination strategies involving targeted inhibitors. Next-generation CDK2/4 inhibitors are an area of active clinical investigation, and efforts are ongoing to evaluate the role of sequential CDK inhibition. Approved and emerging antibody–drug conjugates exploiting novel target antigens have also demonstrated promising clinical activity. These novel agents, as well as further identification and characterization of predictive biomarkers, will hopefully continue to improve clinical outcomes, reduce the incidence of toxicities, and limit the extent of overtreatment in this population. In this Review, we describe the evolving treatment paradigm for patients with metastatic HR + breast cancer in light of the growing armamentarium of drugs and biomarkers that will help to shape the future therapeutic landscape. These strategies are expected to involve tumour molecular profiling to enable the delivery of precision medicine. Patients with advanced-stage hormone receptor-positive (HR + ) breast cancer typically receive first-line treatment with anti-oestrogen-based agents, often combined with a CDK4/6 inhibitor, although resistance remains common. The authors of this Review discuss how a variety of novel endocrine therapies together with tumour molecular profiling could shape the future therapeutic landscape for these patients. Key points Emerging next-generation endocrine therapies, targeted agents and antibody–drug conjugates are changing the treatment landscape of advanced-stage hormone receptor-positive (HR + ), HER2-negative breast cancer. Personalized therapy is predicated on understanding the molecular factors that govern the progression of HR + tumours and drug resistance, exemplified by the regulatory approvals of elacestrant and capivasertib for E