Tamoxifen-Resistant Breast Cancers Become Receptive to New Therapies

DURHAM, N.C. — Breast cancer tumors that stop responding to the drug tamoxifen actually change their cellular characteristics and become responsive to other types of drugs, including Herceptin, according to oncologists at the Duke Comprehensive Cancer Center.

?In the process of becoming resistant to tamoxifen, the tumors alter their qualities and become receptive to Herceptin and other drugs that target the HER-2 receptor,? said Kimberly Blackwell, M.D., assistant professor of oncology at Duke.

Blackwell will present results of the Duke study — conducted in a new mouse strain with tamoxifen-resistant tumors — at the 25th annual San Antonio Breast Cancer Symposium, Dec. 11-14. The research was funded by an NIH Breast Cancer SPORE grant and an unrestricted research grant from GlaxoSmithKline.

?Our findings could hail a major advance for thousands of women who have limited options for cancer treatment, once their tumors spontaneously stop responding to tamoxifen,? Blackwell said. ?We have identified a whole new approach to treating tamoxifen-resistant tumors.?

Tamoxifen and Herceptin are two front-line drugs that shrink breast cancer tumors, yet their mechanisms of action are quite different. Hence, they are used to treat different types of tumors.

Tamoxifen thwarts tumor growth by blocking the action of estrogen, a hormone involved in the growth of up to 80 percent of all breast cancers. The drug works by binding to the estrogen receptor and blocking estrogen from docking to it. Thus, it is called an anti-estrogen. (Receptors are proteins that nestle in the cell membrane and trigger growth and other cellular responses when external chemical signals, such as hormones, activate them.)

Once a woman?s tumor becomes resistant, physicians must try other hormonal therapies that may or may not work. Hence, tamoxifen resistance is considered a major setback in the treatment of breast cancer, said Blackwell.

Surprisingly, however, tamoxifen?s cascade of cellular changes leads to other developments within the cancer cells. Blackwell?s study showed that tamoxifen resistance actually causes breast cells to increase their production of another growth-regulating receptor protein, called HER-2. The drug Herceptin targets the HER-2 receptor and blocks its action, thereby shrinking the tumor.

?Tumors that initially had no response to Herceptin become receptive to its effects, once they have stopped responding to tamoxifen,? said Blackwell. ?The process of becoming tamoxifen resistant appears to make tumor cells over-express the HER-2 protein.?

Just as exciting, she said, a new drug developed by GlaxoSmithKline appears to be even more effective than Herceptin in shrinking tumors that have become resistant to tamoxifen. The new drug, labeled GSK572016, blocks both HER-2 and epidermal growth factor receptor (EGFR), another protein that is over-expressed in a number of cancers.

?The fact that it targets two proteins makes the new drug more effective at shrinking tumors,? said Blackwell.

Specifically, the Duke study showed that mouse tumors treated with Herceptin took about 12 days to re-grow, whereas mouse tumors treated with GSK572016 took 21 days to re-grow. ?This is one of the most significant delays in breast cancer growth that we?ve seen with any drug using this tumor line,? she said.

The Duke team produced its findings by developing a strain of mice that are resistant to tamoxifen?s tumor-shrinking effects. They placed breast tumors in the hind flanks of mice and observed how the tumors responded at a cellular level to each drug and which drug successfully retarded tumor growth.

?We have created an animal model of a woman who has been on tamoxifen for two years and whose cancer has recurred,? said Blackwell. ?It?s a clinically applicable model that is extremely useful for testing new agents.?

Also participating in the study from Duke were Jeffrey Marks, Ph.D, Mark Dewhirst, Ph.D, D.V.M., Gloria Broadwater, Donald McDonnell, Ph.D, and Stacey Snyder, in addition to Neil Spector, M.D., Wenle Xia, Ph.D., and L. Liu, Ph.D., from GlaxoSmithKline in Research Triangle Park, NC.

None of the Duke researchers have financial ties to GlaxoSmithKline.