Use of the anti HER-2/neu antibody Herceptin in the treatment of human breast cancer: biological rationale and clinical results
- DJ Slamon1
© Current Science Ltd 2000
Published: 12 March 2000
The HER-2/neu proto-oncogene encodes a growth factor receptor which is overexpressed in 25-30% of human breast cancers. This pathologic overexpression is associated with a decreased relapse-free as well as overall survival in those patients whose tumors contain the alteration. The overexpression is most often due to amplification in ~ 95% of cases. The association between HER-2/neu amplification/overexpression and clinical outcome suggested that the alteration may play a causal role in pathogenesis. To test the potential role of HER-2/neu overexpression in altering the biological activity of human breast normal and malignant epithelial cells, we conducted a number of in vitro studies in which single-copy, low-expressing cell lines were converted to multiple-copy, high-expressing cells. The biological effects of HER-2/neu overexpression were then measured, including effects on DNA synthesis, cell growth, anchorage-independent growth, tumorigenicity and metastatic potential. Overexpression of HER-2/neu resulted in an increase in those parameters in the malignant cell lines as well as the non-transformed immortalized breast cell lines. In normal primary breast cells there was no evidence of these effects with HER-2/neu overexpression alone.
We also tested the effects of HER-2/neu overexpression on chemosensitivity to a number of agents. There were no effects of overexpression on intrinsic sensitivity or resistance to any of nine chemotherapeutic agents, including anthracycline and taxanes. There were, however, effects on hormone dependence and tamoxifen sensitivity with a direct association between HER 2 overexpression and estrogen independence as well as tamoxifen resistance.
Subsequent to the identification of this alteration and demonstration of the role it plays in the pathogenesis of aggressive breast cancers, we tested a number of antibody reagents directed against the extracellular domain of this receptor from a variety of sources. Many of these antibodies can suppress all of the biological effects induced by HER-2/neu overexpression both in vitro and in vivo. Preclinical studies indicate that the antibodies can be effective in completely suppressing growth of human tumor cells in vitro, as well as breast cancer xenografts when either are growing in vivo. The suppression is specific to cells and tissues overexpressing the HER-2/neu gene. Strategies using anti HER-2/neu in combination with other therapeutic modalities indicates these antibodies can have additive and occasionally synergistic effects with chemotherapeutic agents both in vitro and in vivo. These observations have led to the development of new treatment strategies directed at this molecular alteration, and these strategies have completed clinical testing. The pivotal phase III study comparing best available standard therapy versus best available plus Herceptin demonstrates that this new biological agent improves objective response rates by 54%, response duration by 58% and time to progression by 65%. In addition, initial use of Herceptin as part of the combination therapy results in a decrease in relative risk of death by approximately 25% at two and one half years. The results of this testing have led to the approval of Herceptin, a therapeutic monoclonal antibody effective in HER-2/neu overexpressing breast cancers.