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Gene variation affects tamoxifen's benefit for breast cancer

December 19, 2005

Women with genetic variant were more likely to see their cancer return

One of the most commonly prescribed drugs for breast cancer, tamoxifen, may not be as effective for women who inherit a common genetic variation, according to researchers at the University of Michigan and the Mayo Clinic. The genetic variation affects the level of a crucial enzyme that activates tamoxifen to fight breast cancer.

The study, co-led by researcher James Rae, Ph.D., at the University of Michigan Comprehensive Cancer Center and Matthew Goetz, M.D., an oncologist at the Mayo Clinic, tested the most common genetic variant responsible for lowering the CYP2D6 enzyme, and found that women with this genetic variant were almost twice as likely to see their breast cancer return. Up to 10 percent of women inherit this genetic trait.

Their findings are published in the Dec. 20 issue of The Journal of Clinical Oncology.

"Our group has shown that CYP2D6 is responsible for activating tamoxifen to a metabolite called endoxifen that is nearly 100 times more potent as an anti-estrogen than tamoxifen itself," says Rae, research assistant professor of internal medicine at the U-M Medical School. "Our study suggests that women who inherit a genetic variant in the CYP2D6 gene appear to be at higher risk of relapse when treated with five years of tamoxifen."

Researchers at the U-M Comprehensive Cancer Center were among the group to discover CYP2D6 metabolizes tamoxifen, and they are leading ongoing work looking at how genetic differences affect women's response to tamoxifen. Their research has also found the antidepressant drug Paxil can prevent tamoxifen from being activated, while the antidepressant drug Effexor does not. These drugs, selective serotonin reuptake inhibitors or SSRI's, are often used to treat hot flashes, a common side effect of tamoxifen.

In this current study of 256 women with breast cancer, researchers also found that women with the CYP2D6 variant were less likely to have hot flashes. Any hot flashes among this group tended to be less severe, suggesting that this side effect could predict the gene variation.

Further studies are needed, but researchers hope one day this finding may lead to a genetic test that could help doctors determine which women are most likely to benefit from tamoxifen. This type of test is not currently offered clinically.

Rae and Daniel F. Hayes, M.D., director of breast oncology at the U-M Comprehensive Cancer Center, are part of the Pharmacogenetics Research Network, a multidisciplinary research group conducting a prospective clinical trial to confirm whether genetic testing can be used to identify patients likely to respond to endocrine therapy, including tamoxifen. This group is led by David A Flockhart, M.D., Ph.D. at Indiana University School of Medicine.

More than 210,000 women in the United States will develop breast cancer. Approximately 70 percent of these cancers are fueled by estrogen, many of which are treated with tamoxifen, a drug designed to block the effects of estrogen in breast tissue. The findings from this trial were derived from a large North Central Cancer Treatment Group study in which women were treated with tamoxifen, a pill that is taken daily, for a total of five years.

Additional authors included the following researchers from the Mayo Clinic Cancer Center: Vera Suman, Ph.D.; Stephanie Safgren; Matthew Ames, Ph.D.; Daniel Visscher, M.D.; Carol Reynolds, M.D.; Fergus Couch, Ph.D.; Wilma Lingle, Ph.D.; and James Ingle, M.D., in Rochester, Minn.; and Edith Perez, M.D., in Jacksonville, Fla.; David Flockhart, M.D., Ph.D., and Zeruesenay Desta, Ph.D., both from Indiana University are also co-authors.

University of Michigan Health System