Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications

Recent data show a significant benefit from combining an anti-HER-2 agent with endocrine therapy in HER2-positive and hormone receptor (HR)-positive metastatic breast cancer. However, as the clinical outcomes achieved by these combinations do not favourably match those with chemotherapy, clinicians still perceive HER2-positive breast cancer as an homogeneous group and consider chemotherapy with anti-HER2 agents as the preferred treatment option, regardless of the HR status. Indeed, in HR-positive HER2-positive tumours, chemotherapy with anti-HER2 agents is the backbone of treatment, while endocrine therapy is commonly used in sequence when HR and HER2 are co-expressed rather than as a real alternative. Emerging biological and clinical data challenge this paradigm, suggesting that HER2-positive tumours are rather heterogeneous that HRs co-expression may account for part of this heterogeneity and, finally, that chemotherapy may represent an overtreatment in selected cases. The present review aims to summarise the biological features of HER2-positive breast cancer according to HR status, the role of the bi-directional cross-talk between HER2 and HR pathways on resistance development to anti-HER2 and endocrine therapy, and finally, the novel therapeutic strategies, including but not limited to chemotherapy, targeting these two pathways.