Mayo Clinic reports tamoxifen benefit for breast-cancer patients tied to inherited gene

December 16, 2005

One of the most commonly administered drugs for breast cancer, tamoxifen, may not be as effective for women who inherit a common genetic change, according to researchers at Mayo Clinic and the University of Michigan. The genetic change affects the levels of a crucial liver enzyme, Cytochrome P4502D6, responsible for tamoxifen metabolism.

Up to 10 percent of Caucasian patients have an inherited genetic change that affects tamoxifen metabolism -- and appear to be at higher risk of relapse while receiving tamoxifen.

The study, co-led by Mayo Clinic oncologist Matthew Goetz, M.D., and James Rae, Ph.D., of the University of Michigan, tested the most common genetic change responsible for lowering the CYP2D6 enzyme, and found that women with the genetic change were almost twice as likely to experience breast cancer relapse. Their findings are published in the Dec. 20 issue of The Journal of Clinical Oncology.

"Cytochrome P4502D6 has recently been shown to be a crucial enzymatic step responsible for activating tamoxifen to a metabolite that is nearly one hundred times more potent than tamoxifen," says Dr. Goetz. "Our study demonstrates that women who inherit a genetic change in the CYP2D6 gene that lowers the level of this enzyme appear to be at higher risk of relapse when treated with five years of tamoxifen.

"In addition to being at higher risk of relapse, the women with the genetic change also did not develop one of the most common side effects of tamoxifen -- hot flashes," says Dr. Goetz. "These findings are important, as doctors commonly co-prescribe drugs such as antidepressants for the treatment of hot flashes, and many of these drugs potently inhibit the metabolism of tamoxifen."

More than 210,000 women in the United States develop breast cancer each year. Approximately 70 percent of these are estrogen receptor (ER)-positive cases, many of which are treated with tamoxifen. The findings from this trial were derived from a large North Central Cancer Treatment Group (NCCTG) study led by James Ingle, M.D., in which women were treated with tamoxifen for five years.

Other physicians and researchers involved in the study from Mayo Clinic Cancer Center in Rochester and Jacksonville included 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.; Edith Perez, M.D.; and Dr. Ingle. David Flockhart, M.D., Ph.D., and Zeruesenay Desta, Ph.D., researchers from Indiana University and the Pharmacogenetics Research Network, also collaborated on this study.
The tamoxifen study was funded by the National Institutes of Health, the Commonwealth Cancer Research Foundation and the Breast Cancer Research Foundation.

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