efficacy of herceptin in triple negative breast cancer

Abstract

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using                     breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively                     expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER⁺), HER2⁻ luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts,                     administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown                     in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary                     tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by                     receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of                     adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require                     HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC                     targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1–11. ©2013 AACR.