Herceptin: A Novel Approach to the Treatment of Breast Cancer

By: Gregory I. Berk, MD
Herceptin? (Trastuzumab), the new anti-HER2 monoclonal antibody developed by Genentech, represents a number of innovative "firsts" for the oncology community, and specifically for patients with breast cancer. Herceptin is the first member of a novel class of non-chemotherapeutic agents used for the treatment of breast cancer. It is the first monoclonal antibody to be developed for breast cancer, and the first monoclonal antibody that is targeted to the product of a particular oncogene (a gene giving rise to tumors).
Two recently completed clinical trials have shown promising results for Herceptin, both when used alone and when used in combination with chemotherapy.

There is no better example of the interface of molecular biology research and clinical medicine than the discovery and development of this therapy. One of the more important discoveries in cancer biology was the role of oncogenes in the development of cancer. The HER2/neu gene ("HER2") was found to produce a protein product on the surface of the cell called a receptor. These receptors play an important regulatory role in the growth and development of cells. For unknown reasons, in 25-30 percent of breast cancers, there is an overexpression of HER2, resulting in more protein receptors and uncontrolled growth and multiplication of cancer cells.

For the past several years, doctors have been able to analyze tissue biopsies for the presence of the HER2 gene. The obvious extension of these findings was to use the receptor produced by HER2 as a therapeutic "target" which could possibly delay or even stop the malignant process.


Dr. Dennis J. Slamon and his colleagues at the UCLA Medical Center were the first to make the important clinical observation that overexpression of HER2 is associated with a significantly worse prognosis in breast cancer patients. Specifically, the disease recurs within a shorter period of time and, on average, patient survival is decreased. Indeed, we now use the HER2 assay to assist in predicting clinical outcome and planning treatment regimens.

Scientists from Genentech have created a specific, humanized monoclonal antibody against the protein receptor of HER2, called Herceptin. In rapid time, Herceptin has passed through the rigorous test of Phase I, II, and III clinical trials. The early Phase I trials demonstrated the drug was safe and well tolerated, and the more recent Phase II and III clinical trials have shown definite activity in breast cancer patients.

In one pivotal Phase III clinical trial, using Herceptin as a single agent, 222 patients were treated (all HER2 "overexpressors." with metastatic breast cancer) at 54 centers. Most patients had been heavily pretreated with at least two prior chemotherapy regimens. The overall response rate was 15 percent. The median duration of response was 9.1 months. In an even more important Phase III trial, Herceptin was given with chemotherapy (either Taxol or Adriamycin/Cytoxan) in the first line treatment of breast cancer. This trial found that the combination of Herceptin plus chemotherapy produced a 49 percent response rate, with 78 percent of patients alive at the 1-year mark. This was significantly better than the control group of chemotherapy alone, which had only a 32 percent response rate, with 67 percent of patients alive at the 1-year mark.

While only 25-30 percent of breast cancer patients may overexpress the gene and thus be candidates for therapy, all patients in this group should be considered candidates for this therapy. The treatment is well tolerated, the more common side effects being fever, chills, and pain during the infusion. It?s worth noting that these symptoms are more common with the first infusion and diminish with subsequent treatments.

The most significant toxicity observed with Herceptin is cardiac dysfunction. This is most important in those patients who receive Herceptin in conjunction with an anthracycline (adriamycin), which can also be associated with cardiac dysfunction. For this reason, it will most likely be recommended that the drug be given with a taxane (Taxol or Taxotere) and not with an anthracycline.

In summary, the addition of Herceptin to the practice of oncology not only demonstrates the clinical benefits of unique scientific research, but also provides greater hope to the many patients currently living with metastatic breast cancer.

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