Saturday 17th December, 2005
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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.
References:
Matthew P. Goetz, James M. Rae, Vera J. et al. Pharmacogenetics of
Tamoxifen Biotransformation Is Associated With Clinical Outcomes of
Efficacy and Hot Flashes. JCO Dec 20 2005: 9312?9318.
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