Human epidermal growth factor receptor-2 and endocrine resistance in hormone-dependent breast cancer

Abstract

Endocrine therapies are the main treatment strategies for the clinical management of hormone-dependent breast cancer. Despite prolonged time to recurrence in the adjuvant setting and the initial clinical responses in the metastatic setting, many patients eventually encounter tumour relapse due to acquired resistance to these agents. Other patients experience a lack of tumour regression at the beginning of treatment indicating de novo resistance that significantly limits its efficacy in the clinic. There is compelling evidence that human epidermal growth factor receptor-2 (HER2) overexpression contributes to resistance to endocrine therapies in oestrogen receptor-positive (ER+) breast cancer. ER+/HER2+ tumours comprise about 10% of all breast cancer cases and about 60% of the whole set of HER2+ tumours. Most patients with primary ER+/HER2+ disease will receive antibody-based HER2-targeted therapy, but this is generally for no more than one year while endocrine treatment is usually for at least 5 years. A number of HER2-kinase inhibitors are also now in clinical use or in clinical trials, and the interaction of these with endocrine treatment may differ from that of antibody treatment. In this review article, we aim to summarise knowledge on molecular mechanisms of breast cancer resistance to endocrine therapies attributable to the impact of HER2 signalling on endocrine sensitivity, to discuss data from clinical trials addressing the role of HER2 in the development of endocrine resistance in the metastatic, neoadjuvant and adjuvant settings and to explore rational new therapeutic strategies.

Keywords: breast cancer; endocrine therapies; human epidermal growth factor receptor-2; oestrogen receptor; resistance.

Figure 1

Main events and response endpoints over the course of endocrine treatment settings in breast cancer. Endocrine resistance is manifested clinically as an increase in tumour volume, relapse and progression in the neoadjuvant, adjuvant, and metastatic treatment setting, respectively. Biological endpoints have, also, been considered as an indication of endocrine treatment resistance. For instance, Ki67 is often measured either as a static marker of proliferation, or as a dynamic surrogate marker of drug response, when the expression levels are measured at multiple times during neoadjuvant treatment.

Figure 2

Crosstalk between ER and HER2 signalling pathways and its role in endocrine resistance and therapeutic agents that block specific molecules. A more detailed description is presented in the main text.