Gene Test Might Predict Tamoxifen's Effectiveness

TUESDAY Oct. 6, 2009 -- A genetic variant seems to predict resistance to the breast cancer drug tamoxifen, German researchers report.

The findings, which appear in the Oct. 7 issue of the Journal of the American Medical Association, could allow clinicians to predict which women will benefit most from the drug, which has been the gold standard of breast cancer care for the past 25 years. Women who do carry the gene variant may be candidates for alternative treatments.

The gene affects the activity of the CYP2D6 enzyme, which converts tamoxifen into its metabolite, endoxifen. It is this metabolite that allows the drug to work its magic against breast tumors.

"This is really the largest study that's been done in this area," noted V. Craig Jordan, scientific director of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. "It's now clear if you don't have the ability to create endoxifen out of tamoxifen, you don't have a good response rate. This is really important because for women who are taking the drug for five years, you better know it's going to work for you."

And for women who won't have the desired therapeutic response to tamoxifen, there are now other options, namely in the form of medicines called aromatase inhibitors, which, like their older cousin tamoxifen, inhibit the effect of estrogen on cancer.

"In postmenopausal women, if you've got this aberration in your metabolism of tamoxifen, you could be offered an aromatase inhibitor, so there is something one could do for a person at this particular point," Jordan said.

Jordan is known as the "father of tamoxifen" because he helped develop the drug.

On the other hand, if your body is able to metabolize tamoxifen effectively, Jordan added, "it's as good a therapy as you can get."

Although tamoxifen has an excellent track record, many women do develop resistance to the drug. And researchers are in the process of calibrating when tamoxifen might be more appropriate to a situation and when aromatase inhibitors would better serve the patient.

The authors looked back at the cases of 1,325 women, almost all postmenopausal, who had been diagnosed with estrogen-receptor-positive, early-stage breast cancer.

Women were tested for CYP2D6 variants and divided into three groups based on the results: extensive metabolizers, extensive/intermediate metabolizers or poor metabolizers.

After an average follow-up of 6.3 years, women who were better metabolizers of CYP2D6 were less likely to see their cancer recur: 14.9 percent versus 20.9 percent in the intermediate group and 29 percent in the poor-metabolizer group. Low metabolizers also had lower rates of event-free survival, but no difference in overall survival. The authors did point out that the follow-up period was not long enough to actually determine differences in overall survival.

One expert had a mixed response to the new findings.

"I think this is real. I think these variants have some impact on how effective tamoxifen is for a given woman, but I don't think it's an all or nothing, either you respond or you don't. I think there are gradations of response," said Dr. Mary Daly, senior vice president of population science and director of the Cancer Prevention and Control Program at Fox Chase Cancer Center in Philadelphia.

But she also said she would like to see prospective studies before changing how she practices medicine.

"I'm not too sure how important this will be clinically because we're all sort of switching to aromatase inhibitors anyway," she added. "In general, though, it signals a movement towards personalizing therapies to genetic variants."

For his part, Jordan predicts that using genetic testing to help determine treatment will become the standard of care within just six months to a year. The cost should not be prohibitive, he added, especially as the test becomes more widely available.

Five of the study authors, in conjunction with the Mayo Clinic, have filed patent applications related to tamoxifen and CYP2D6.

More information

There's more on tamoxifen at the U.S. National Cancer Institute.

Posted: October 2009


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