Trastuzumab (Herceptin) Boosts Chemotherapy
A study just published in the New England Journal of Medicine has found that the HER2 monoclonal antibody called trastuzumab-more commonly known as Herceptin-may improve the effectiveness of chemotherapy for certain women with metastatic breast cancer.
Specifically, a team of California researchers found that trastuzumab appeared to make chemotherapy more effective in women whose breast cancer exhibits an overabundance ("overexpression") of a protein called HER2-which occurs in up to a third of all breast cancers.
Antibodies are proteins made by the body's own natural immune system. Antibodies attack foreign and infectious agents called antigens. Monoclonal antibodies are antibodies engineered through biotechnology instead of being produced naturally. They imitate immune system antibodies by providing specific actions against cancer cells.
Trastuzumab is a monoclonal antibody that attaches itself to HER2 protein receptors on the surface of cancer cells. When there is an overexpression or abundance of these receptors, it is easier for trastuzumab to find targets. By binding to the HER2 proteins on the surface of these cancer cells, trastuzumab is able to slow their growth and reduce the spread of tumors.
In the above-mentioned study, Dr. Dennis Slamon from the University of California at Los Angeles and colleagues conducted a phase III trial involving 469 breast cancer patients with HER2-positive metastatic disease. Half of the patients were given chemotherapy alone and half where given chemotherapy with trastuzumab.
The researchers found that the addition of trastuzumab to chemotherapy extended the median time to disease progression from 4.6 months to 7.4 months, and increased the treatment response from 32 percent to 50 percent. Death rates were also lower in the trastuzumab group (22 percent versus 33 percent after one year).
However, there was an increased risk of heart damage with the trastuzumab group, the researchers reported. By the end of the trial, 18 of the patients (8 percent) had to discontinue trastuzumab treatment. "The mechanism of the cardiotoxicity of trastuzumab is unknown," they acknowledged.
Recently, Genentech, the company that manufactures and markets Herceptin, issued a warning of its own. While Herceptin has been used to treat more than 25,000 women since it was first approved by the FDA in late 1998, Genentech reported that 62 patients have had serious problems with the drug. Fifteen patients eventually died.
All of the patients experienced allergic reactions to the drug after the initial dose, and some of the deaths may have been the result of other complications from their cancers. However, both Genentech and the FDA agree that Herceptin is one of the "least toxic" of the breast cancer drugs currently on the market, as well as one of the most promising.
In addition, the FDA took the unusual step of publicly backing the continued use of Herceptin after the manufacturer's warning because it noted that such reactions to the drug are "rare" and occur at similar levels with other cancer drugs. Furthermore, the agency said, the drug's promising results in breast cancer studies simply cannot be ignored.
At a recent Department of Defense Breast Cancer Research Program meeting in Atlanta, Dr. Michael DiGiovanna of the Yale University School of Medicine presented the results of a study that found that the HER2 protein receptors on cancer cells may be in either an "active" or a "passive" state.
DiGiovanna said his research found that the majority of tumors demonstrating an overexpression of the HER2 protein might actually have the protein in a less aggressive resting or passive state. In fact, he found that only 12 percent of the tumors with the overexpression of HER2 had the protein in the more aggressive active state.
The use of Herceptin, particularly when used in conjunction with other anticancer drugs, can have some significant side effects, including a risk of heart muscle damage. Therefore, DiGiovanna said, his findings could help doctors determine which patients might benefit more from Herceptin (those with "active" HER2 proteins) and which patients would be better served by other treatments for their disease.
Testing for overexpression of the HER2 protein is done on tumor tissue and should ideally be performed at the time of diagnosis. Patients who want their HER2 status checked should ask their physician to have testing done at the time of biopsy or surgery, or on their stored tumor tissue.
Pathology labs often keep biopsy tissue for a number of years, so your tissue can potentially be evaluated for HER2 protein overexpression well after your initial diagnosis. Your doctor can request that the HER2 test be performed on the stored tissue sample, commonly called "archived tissue."
If you are told that your tissue is no longer being stored, you may want to consider requesting a new biopsy. Fortunately, newer, less invasive methods of taking breast tissue samples are now available, including fine-needle aspiration and core biopsy.
Once your tissue is obtained, either from a new biopsy or from archived tissue, the HER2 test is performed by staining the tissue with a specific solution, or reagent. The test is then evaluated by a pathologist, who looks for highlighted areas where high levels of overexpression are present. Depending on the level of staining, your tissue sample may be classified as HER2 positive, which means that you may be a candidate for Herceptin monoclonal antibody therapy.
SOURCES:
New England Journal of Medicine, March 15, 2001; 344:783-792, 841-842
The U.S. Food and Drug Administration (www.fda.gov)
Department of Defense Breast Cancer Research Program meeting, June 9, 2000, Atlanta, GA
Genentech Corporation (www.herceptin.com)
"Therapeutic and Diagnostic Monoclonal Antibodies for Cancer," Decision Resources, Inc.
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