Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature

SIMPLE SUMMARY: In the last decades, tremendous advances have been made in understanding HER2-positive breast cancer biology, with a progressive improvement in survival rates of patients with this breast cancer subtype. However, a not negligible proportion of patient with HER2-positive breast cancer will eventually relapse, and metastatic HER2-positive disease is still to be considered an incurable condition, thus highlighting the imperative need to further improve our understanding in this regard. In this context, there is growing knowledge that HER2-overexpressing breast tumors are highly heterogeneous, and the co-expression of hormone-receptors may account, at least in part, for this heterogeneity. The aim of the present work is to review preclinical and clinical evidence on HER2-positive/hormone-receptor positive breast cancer, focusing on studies investigating both activity and efficacy of various combination of treatment strategies, including anti-HER2 drugs, hormonal treatments and other targeted agents, such as CDK inhibitors, both in the early and advanced setting. ABSTRACT: Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.