Description
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. For reasons no one understands a fraction of breast cancers, as part of their development, undergo a 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 HER-2-positive breast cancer.
Latest Research Directions
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 to chemotherapy alone.
The U.S. studies – the North Central Cancer Treatment Group and the National Surgical Adjuvant Breast and Bowel Project trials, both sponsored by the National Cancer Institute – looked at treatments of the chemotherapy drugs doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab. The European study, the Herceptin Adjuvant Trial, compared chemotherapy followed by trastuzumab to chemotherapy alone. For many women with HER2-positive breast cancer, these results may mean a significant improvement in survival.
Scientists see the results from these studies as providing new challenges and opportunities. One important goal will be to find ways to best use trastuzumab. There will be studies looking at individual tumors to figure out which patients are most likely to benefit from the drug, and there will be efforts to create new chemotherapy “backbones” that have even fewer side effects than those currently used. Others wonder if known cancer-causing genes that determine behavior in malignancies might provide clues about why someone benefited from trastuzumab and someone else did not, and who might do well with chemotherapy alone. Researchers also are planning studies to determine the appropriate duration of treatment with trastuzumab, and ways to identify which patients are at risk for significant cardiac toxicity, which the studies indicated occurred in a relatively small percentage of individuals.
Scientists will continue to try to find improved next-generation drugs aimed at the HER2 protein alone and in combination with trastuzumab.
Breast cancer researchers are encouraged and buoyed by the successes in treating HER2-positive cancers. Many say these will open up opportunities and will help set directions for new research programs aimed at the vast majority of breast cancers that are HER2-negative. Of the four major types, only one is HER2-positive, and different treatment programs may be needed for each. Scientists are hoping to be able to refine their studies, and ask questions that are more specific about what types of patients may benefit from certain treatments, for example, and how much treatment is enough. What novel treatments can be developed for subsets of patients? Can appropriate molecular targets be identified for new therapies?
Some scientists believe that these results indicate that there may be relatively few key genes controlling the activity of the cancer, and perhaps not all of the genes in a particular cancer pathway need to be targeted for a therapy to be effective in controlling the disease.
Discovery and Early Research
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 call neu that appeared to cause breast cancer in the animals. Soon after, scientists showed that human cells in culture could be turned cancerous by overexpressing 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 and his group at the University of California, Los Angeles showed that node-positive breast cancers often overexpressed the HER2/neu oncogene, meaning 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 and a target for therapy.
Slamon and South San Francisco-based 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.
Researchers developed tests to determine a woman’s cancer’s HER2 status, and an immunohistochemistry test to determine if a tumor might benefit from therapy.
Two early studies by Melody Cobleigh at Rush Presbyterian-St. Luke’s Hospital in Chicago and Charles Vogel at Columbia Cancer Research Network of Florida looked at monoclonal antibody therapy alone in women with metastatic breast cancer who had failed other therapies. Some patients’ tumors stopped growing.
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 antibody with chemotherapy. This led to FDA approval in 1998 of trastuzumab for women whose breast cancer had metastasized and had strong HER2 expression.