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Mutation in CYP2D6 May Influence Tamoxifen Efficacy; Some Antidepressants May Play Role

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The widely used breast cancer drug tamoxifen may be less effective in women with a common mutation in the CYP2D6 gene, according to a new study.

The research also confirmed an earlier study showing that selective serotonin reuptake inhibitors such as Paxil and Zoloft, which block the CYP2D6 enzyme, might also have a negative effect on tamoxifen efficacy.

Though the findings are still preliminary, if verified in an ongoing retrospective study by the same researchers they may enable oncologists to consider alternatives to tamoxifen for women who carry the mutation. The results might also encourage doctors to prescribe antidepressants that do not inhibit the CYP2D6 enzyme for all women taking tamoxifen.

Researchers from Johns Hopkins, Indiana University, and the University of Michigan presented the study, which has been submitted to a journal for publication, at the annual American Society of Clinical Oncology conference in New Orleans last week.

Tamoxifen is used to prevent breast cancer recurrence or metastasis, and to prevent breast cancer in women at high risk for the disease. As many as half of the 200,000 new breast cancer patients in the United States every year might be recommended to take tamoxifen, according to Vered Stearns, one of the study leaders and an assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

But CYP2D6, which converts tamoxifen into endoxifen, one of its active forms, may throw a monkey wrench into the works.

To arrive at their results, the scientists studied 80 women who took tamoxifen daily for four months. About a third of them carried a certain CYP2D6 mutation, and researchers found that endoxifen was greatly reduced in women with the CYP2D6 mutation in both copies of the gene. The team estimated that approximately 40 percent of women carry the mutation.

Also, endoxifen was reduced in women taking Paxil, and somewhat reduced in those taking Zoloft — SSRIs made by GlaxoSmithKline and Pfizer, respectively — regardless of whether they carried the mutation. Both inhibit the CYP2D6 enzyme, according to Stearns. It was least reduced by Effexor, made by Wyeth-Ayerst.

This confirmed the results of a study published in the Journal of the National Cancer Institute last year by Stearns and colleagues. The confirmed findings are significant because at least 20 percent of women who take tamoxifen also take antidepressants, mostly for hot flashes, a common side effect of the cancer drug, and depression.

To be sure, the researchers have not yet proven that this mutation reduces the effectiveness of tamoxifen, Stearns said. "In the next few months, we will have more data from the studies that we are conducting now, and then we will be able to come back with recommendations," Stearns told Pharmacogenomics Reporter. Her team is currently collecting samples from women who have been treated with tamoxifen to see whether those who experienced a recurrence carry the CYP2D6 mutation.

If this is true, the findings may enable doctors to alter their treatments for women with the mutation. They might recommend that postmenopausal women take aromatase inhibitors instead of tamoxifen, or that pre-menopausal women have their ovaries suppressed in addition to taking tamoxifen.

Also, women on tamoxifen might prefer to take antidepressants that do not inhibit CYP2D6 significantly, such as Effexor, or Celexa, which is made by Forest Pharmaceuticals, Stearns said. She does not currently recommend that women on SSRI therapy switch drugs.

A diagnostic for the CYP2D6 mutation, which Stearns does not recommend based on the present results, is currently not commercially available, although some academic centers might be able to provide it, she said.

— JK

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