The HER2 (human epidermal growth factor receptor 2) gene is part of a family of genes that play roles in regulating cell growth. The protein it makes is a tyrosine kinase growth factor receptor that a number of normal tissues express and which probably has a role in normal cell function, regulating growth and proliferation.
A fraction of breast cancers, as part of their development, undergo gene amplification. Instead of having two gene copies of the HER2 gene in a normal cell, there are multiple copies. As a result, there is far more expression of the HER2 protein on the cell surface, resulting in aberrant cell growth regulation. Tumors are faster growing, more aggressive and less sensitive to chemotherapy and hormone therapy.
An estimated 20 to 25 percent of breast cancers make these extra copies of the HER2 gene. A normal breast cell might have 20,000 HER2 receptors; a breast cancer cell could have as many as 1.5 million. Approximately 40,000 women are diagnosed each year in the United States with HER2-positive breast cancer.
Early Research and Discovery
The story of HER2 and breast cancer exemplifies what scientists hope to achieve on a broader scale in all cancers and in translational medicine. In the 1980s, scientists, attempting to uncover new cancer-causing oncogenes, discovered a rat gene called neu that appeared to cause breast cancer in animals. Soon after, scientists showed that human cells in culture could be turned cancerous by over expressing the equivalent gene in humans, called HER2/neu. In animal models, antibodies against the HER2/neu gene caused cancers to shrink.
In 1987, Dennis Slamon, M.D., Ph.D., chief of the division of hematology and oncology at the University of California Los Angeles, showed that node-positive breast cancers often over expressed the HER2/neu oncogene, meaning that there were more copies than normal of the HER2 protein on the cell surface. He found that women whose breast cancer had more copies of the HER2 gene spread the fastest and had a worse prognosis. This identified an important subset of breast cancers as a target for therapy.
Trastuzumab
Slamon and Genentech developed mouse monoclonal antibodies for HER2 in an attempt to block the receptors and their growth signal. Genentech subsequently "humanized" the antibody, creating a monoclonal antibody called trastuzumab that bound to the HER2 protein on the surface of cancer cells, leaving normal cells alone. Subsequent work in the laboratory dish showed that even though normal cells have some minor degree of HER2 expression, the antibody was only effective in breast cancer cells that made dramatically more protein than normal.
Slamon conducted a clinical trial comparing chemotherapy and trastuzumab as a first treatment for HER2-positive women with metastatic breast cancer to chemotherapy alone. He found that the response rate and the duration of response were all markedly improved by combining the antibody with chemotherapy. This led to FDA approval in 1998 of trastuzumab for women whose breast cancer had metastasized and had strong HER2 expression.
In 2005, results from three clinical trials reported in the New England Journal of Medicine, involving more than 6,500 women with early stage breast cancer, showed that the drug trastuzumab (Herceptin) cut the risk of relapse in half. That is, the results, from two trials in the United States and one in Europe, found that for many women with early-stage HER2-positive breast cancer, which tends to return despite treatment, adding trastuzumab to chemotherapy could cut the rate of cancer recurrence by 50 percent compared with chemotherapy alone.
In 2006, Slamon presented new data at the San Antonio Breast Cancer Symposium on 3,200 women who had been given chemotherapy plus trastuzumab or chemotherapy alone. At three years, the risk of death was reduced by 40 percent among patients with chemotherapy plus trastuzumab; 92 percent of the patients were still alive at three years.
HER2 as a Prognostic Marker
More recent research has focused on HER2 as a prognostic marker for benefit of certain cancer therapies.
At the 2007 San Antonio Breast Cancer Symposium, Slamon presented data that showed the benefit of adjuvant anthracycline-based therapy appears to be restricted to women with HER2 positive breast cancers. Anthracycline based therapies tend to improve survival by about 4 to 5 percent, but Slamon claims that the improvements are restricted to HER2 positive breast cancers. However, this finding is still in dispute.
At the American Association for Cancer Research 2008 Annual Meeting, researchers presented data that showed the benefit of a HER2 peptide E75 vaccine was restricted to patients with HER2-positive breast cancer, where the therapy reduced mortality by half. The effect was not as pronounced in patients who did not have HER2 positive breast cancer.