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Silver Lining Found in Resistance to Tamoxifen

Mouse study finds tumors become susceptible to other drugs

FRIDAY, Dec. 13, 2002 (HealthDayNews) -- New research suggests that when a door closes in breast-cancer treatment, a window may open.

A large number of women treated for breast cancer with the drug tamoxifen develop a resistance to the drug after several years. The new study suggests, however, that these women may then become eligible for other cancer-fighting drugs that they may have not been able to take before -- and which may help in the fight against recurrence.

While it is bad news to find tamoxifen no longer effective and tumors grow back, the news is not all bad, says Dr. Kimberly Blackwell, an assistant professor of oncology at Duke Comprehensive Cancer Center in Durham, N.C. "In the process of becoming resistant to tamoxifen, these tumors become receptive to other treatment."

Blackwell presented a poster on her research group's findings today at the San Antonio Breast Cancer Symposium, a gathering of specialists treating the disease.

The researchers studied mice that they developed to have human breast tumors in their hind flanks. When the mice became resistant to tamoxifen, meaning the drug was no longer effectively stopping the growth of cancerous cells, the tumor altered, Blackwell explains.

The researchers found all the tumors in the 27 mice they tested became receptive to drugs that target the HER-2 receptor, such as Herceptin, she says. About 75 percent of the women who were candidates for treatment with tamoxifen would have been HER-2 negative prior to their treatment, she says, meaning they could not have benefited from this other class of drugs before.

The two drugs -- tamoxifen and Herceptin -- are typically used to treat different kinds of breast tumors. Women whose tumors grow because of estrogen have proteins nestled in the cell membrane that trigger growth when they connect with estrogen. Tamoxifen, known as an anti-estrogen, blocks this from happening.

Blackwell's study found that when womens' tumors stopped responding to tamoxifen, their breast cells increased production of another growth-regulating receptor protein, called HER-2. Herceptin could then be used to block this action and shrink the tumor.

"I think it makes a lot of sense," says Dr. David Nathanson, an oncologist at Henry Ford Hospital in Detroit. "We've suspected this for quite a while."

He says that there is a known inverse relationship between the expression of HER-2 receptors and estrogen receptors, so that when one expresses too much, the other one does not usually express as much.

Although he would like to see clinical research in humans, when "tamoxifen is no longer working, we may be able to use Herceptin," he says.

Dr. Eric Rowinsky, director of clinical research at the Cancer Therapy and Research Center in San Antonio, is more cautious. "The ramifications of any phenomenon demonstrated in mice, even with human tumors, we never really know. I can't say it will be fulfilled in the clinic" (in studies on humans), he says.

Nathanson says if Herceptin becomes an option, it would be good news, but women should realize that even now when tamoxifen fails, physicians have a number of other medications they can try. "This is just another modality," he says.

In another finding related to the same research, the Duke investigators used a new drug being tested by GlaxoSmithKline, labeled as GSK572016, that works similarly to Herceptin.

They found this drug blocked not only HER-2 but another protein over-expressed in many cancers known as EGFR (epidermal growth factor receptor), Blackwell says, making it was exceptionally effective at shrinking tumors.

This new drug, if approved by the Food and Drug Administration, may become a good new tool to fight cancer, she says.

For now, the findings of the study suggest that if a woman has become receptive to tamoxifen, she should be tested by her doctor to see if she can now receive Herceptin, Blackwell says. "It's worth re-checking the HER-2 status of a patient initially not eligible for Herceptin," she adds.

The research for this study was funded by a grant from the National Institutes of Health and an unrestricted research grant from GlaxoSmithKline. It will be published in a future issue of Breast Cancer Research and Treatment.

What To Do

Those interested in tamoxifen resistance can click on the Journal of the American Medical Association. The National Cancer Institute has lots of information on the disease.

SOURCES: Kimberly Blackwell, M.D., assistant professor of oncology, Duke Comprehensive Cancer Center, Durham, N.C.; David Nathanson, M.D., oncologist, Henry Ford Health Center, Detroit; Eric Rowinsky, M.D., director of clinical research, Cancer Therapy and Research Center, San Antonio, Texas; Dec. 13, 2002, poster presentation, San Antonio Breast Cancer Symposium
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