Bad combo? Some antidepressants may hamper breast cancer drug.

By impeding estrogen's cancer-promoting properties, the drug tamoxifen has enabled thousands of breast cancer patients to fend off recurrences. But taking tamoxifen increases the frequency of hot flashes, and many women use antidepressants to limit this side effect.

Researchers now report that popular antidepressants called selective serotonin reuptake inhibitors (SSRIs) might diminish the effectiveness of tamoxifen by limiting its conversion into medicinally important agents.

David A. Flockhart of the Indiana University School of Medicine in Indianapolis and his colleagues there and elsewhere measured one of these compounds, called endoxifen, which binds to estrogen receptors on cells and slows cancerous growth. In the Jan. 5 Journal of the National Cancer Institute, they report that women taking tamoxifen and an SSRI had lower blood concentrations of endoxifen than did similar women on tamoxifen who weren't using an SSRI.

The scientists also determined that a woman's genes can hinder her conversion of tamoxifen to endoxifen. Women with certain variant forms of a gene called CYP2D6 showed diminished endoxifen concentrations. Lab studies had shown that the enzyme encoded by CYP2D6 is one of the substances that break down tamoxifen to create endoxifen.

About two-fifths of women have one of the enzyme-disabling variants of CYP2D6, says Flockhart. The findings could explain some of the variability in tamoxifen's effectiveness from patient to patient, he says.

Flockhart and his colleagues identified 80 women, average age 57, who had breast cancer and were just starting on tamoxifen. Some of the women were taking SSRIs, and some weren't; some in each group had a normal CYP2D6 gene, and some carried an enzyme-disabling variant. Over the following year, the scientists periodically recorded endoxifen concentrations in the women's blood.

The data showed that 48 of these 80 women had a normal CYP2D6 gene and thus probably made a full complement of its corresponding enzyme. After 4 months on tamoxifen, these women had nearly twice as much circulating endoxifen as did women who had inherited one of the enzyme-disabling variants of CYP2D6 from just one parent. Compared with women who had inherited variant forms from both parents, those with the normal gene had four times as much endoxifen in their blood.

Twelve of the 48 women with a normal CYP2D6 gene were also taking an antidepressant. Ten were on an SSRI--paroxetine (Paxil) or sertraline (Zoloff). The two others were getting venlafaxine (Effexor), which differs slightly from the SSRIs. Paroxetine and sertraline use coincided with significantly diminished endoxifen concentrations in blood, but venlafaxine didn't. The findings bolster test-tube studies in the 1990s that suggested that SSRIs could suppress the CYP2D6 enzyme.

The study raises hard questions about prescribing SSRIs for breast cancer patients with hot flashes, says Charles L. Loprinzi of the Mayo Clinic in Rochester, Minn. But it's encouraging that venlafaxine appears to leave the CYP2D6 enzyme alone, he says.

At a recent meeting, Mayo Clinic researcher Matthew P. Goetz unveiled data showing that breast cancer patients taking tamoxifen survived longer if they had a normal CYP2D6 gene rather than an enzyme-disabling variant.

If scientists can conclusively connect tamoxifen's effect on breast cancer recurrences and deaths to variants of this gene, Flockhart says, doctors might better identify which patients would benefit most from the drug.