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Predicting Resistance to the Breast Cancer Drug Tamoxifen

By Nancy Touchette


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Breast Cancer
Drugs
Personalized Medicine

The drug tamoxifen is widely used to treat certain breast tumors and to prevent their recurrence. However, half of all recurrences in breast cancer patients are resistant to the drug and often more aggressive tumors result. Now two new studies suggest tests to predict who will benefit from tamoxifen and also explain why the drug so often fails.

Approximately 70 percent of all breast tumors depend on estrogen. The tumors produce estrogen receptors that can turn on genes that promote tumor growth when the hormone is present. Tamoxifen halts tumor growth by blocking the estrogen receptor.

A new study by Rob Michalides and his colleagues at the Netherlands Cancer Institute in Amsterdam offers an explanation of what is happening when tamoxifen fails to work.

The researchers report in Cancer Cell that women who develop tamoxifen resistance produce unusually high levels of a molecule called protein kinase A, or PKA, which alters the estrogen receptor on the surface of a breast tumor and changes its shape. When this happens, tamoxifen activates the estrogen receptor system and promotes tumor growth rather than stopping it.

“We are now trying to develop a test to measure these altered estrogen receptors,” says Michalides. “We predict that those patients with this alteration would be better off with other drugs.”

For example, Michalides found that the altered form of the estrogen receptor can be inhibited by another drug called Fulvestrant. Patients resistant to tamoxifen might be better off with this or similar drugs, he says.

In a related study, also appearing in Cancer Cell, Dennis Sgroi of Massachusetts General Hospital in Boston, and his collaborators compared gene activity in tamoxifen-sensitive and tamoxifen-resistant tumors. They found two genes that predict whether a tumor is likely to recur.

Tamoxifen resistance apparently develops when a gene called HOXB13 is highly active and a gene called IL17BR is inactive. By comparing the ratio of activity of the two genes in a set of tumor samples from 20 patients, researchers were able predict tumor recurrence with more than 80 percent overall accuracy.

“This is the closest thing we have to individualized molecular medicine for treating breast cancer,” says Sgroi. “Perhaps we have all the correct therapies already out there for treating breast cancer. But we may not be targeting them correctly.”

Sgroi is collaborating with researchers at Arcturus Bioscience, Inc. in Carlsbad, California, to rapidly develop a test to predict tamoxifen response in breast cancer patients. Such a test could be used to help doctors decide on an appropriate course of treatment, although it is probably a few years away from general use.

The researchers do not yet know how the two studies are related. Although each group identified different genes that could predict outcome following tamoxifen therapy, it is possible that genes identified so far are part of the same pathway or interacting pathways that ultimately lead to tumor growth.

Most importantly, both studies suggest that tamoxifen resistance is a property of the tumor from the outset and does not arise in the course of tamoxifen treatment.

“We have not had a chance to compare the data from the two studies,” says Michalides. “But this is something we will be looking at.”

Michalides, R. et al. Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer. Published online in Cancer Cell (June 2004).
Ma, X.J. et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Published online in Cancer Cell (June 2004).

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