Treatment of HER2-overexpressing breast cancer

Abstract

The HER family of receptors consists of four closely related type 1 transmembrane TK receptors: HER1 (EGFR), HER2, HER3 and HER4. Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend. Aberrant HER2 expression and/or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or the recruitment of antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners. Novel strategies against HER2 include HER tyrosine kinase inhibitors, HSP90 inhibitors and antibody–chemotherapy conjugates. This latter approach is exemplified by T–DM1, a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease. In addition, pertuzumab, an mAb that directly inhibits the formation of HER2 dimers including the HER2:HER3 dimer, offers a unique mechanism of HER3 inhibition. All these approaches have shown substantial clinical activity in patients refractory to trastuzumab. It is anticipated that with the increased availability of novel anti-HER2 agents together with a better understanding of the mechanisms of resistance to anti-HER2 agents we should be able to further improve the outcome of patients with HER2 breast cancer. There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.