Understanding Why Herceptin Works - and Doesn't

Ever since it came on the market, researchers have been trying to understand why the breast cancer drug Herceptin® (trastuzumab) works for some women and not others. However, a team of Swiss researchers may have eliminated at least one theory for its frustrating level of ineffectiveness.

Herceptin was the first so-called monoclonal antibody drug to be developed as a treatment for breast cancer. Specifically, Herceptin targets cancer cells that have an abundance of sites called HER2-neu oncogenes on their cell surface. When many of these sites are present ("overexpressed"), it is easier for Herceptin to find targets to latch onto. It then inhibits the cancer cells' ability to grow and proliferate.

Studies have shown that an overexpression of the HER2-neu oncogene occurs in at least one-third of all women with breast cancer. Therefore, developing monoclonal antibodies such as Herceptin that specifically attack HER2-neu has become an extremely important area of breast cancer research.

Unfortunately, while a third of women with breast cancer have this HER-2-neu overexpression-and thus should potentially benefit from Herceptin-a much smaller percentage actually show a significant positive response to the drug.

One theory for this lack of effectiveness has been that the HER-2 oncogene may be abundant in the initial breast tumor, but not in the cancer cells that have migrated (metastasized) to other parts of the body.

However, a new study by a team of Swiss researchers may have eliminated that hypothesis.

Writing in the Journal of the National Cancer Institute, Ronald Simon, Ph.D., and Dr. Guido Sauter of the University of Basel and colleagues found that tumors that have spread to other parts of the body often had genetic characteristics similar to the primary breast tumor.

Specifically, they found that more than three-quarters of the HER-2 positive women in their study had entirely HER-2 positive metastases. Therefore, Herceptin should be equally effective on their distant metastases as it is on the primary tumor. But all-too-often it is not.

Simon and Sauter concluded that researchers will therefore have to look elsewhere to determine why Herceptin does not work for many HER-2-positive women, especially those whose cancer has spread beyond the primary tumor in the breast.

In an accompanying editorial, Dr. Ann Thor of the University of Oklahoma College of Medicine cautioned that the Swiss researchers focused solely on breast cancer that had spread to surrounding lymph nodes, rather than on tumors present on distant organs. Thor said more research is needed to determine the HER-2 concentration on these faraway tumors.

SOURCES:
Journal of the National Cancer Institute, August 1, 2001; 93:1141-1146
National Cancer Institute (http://www.nci.nih.gov)

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