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SAN ANTONIO -- The antidepressant venlafaxine (Effexor), often given to breast cancer patients to treat the hot flashes associated with tamoxifen therapy, might reduce the effectiveness of the drug, a researcher said here.

In a multicenter prospective study, venlafaxine inhibited the metabolism of adjuvant tamoxifen by lowering the concentration of the drug's active metabolite, endoxifen, according to Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minn.

The effect – caused by an inhibition of cytochrome P450 2D6 (CYP2D6) -- is small but statistically significant, Goetz reported in a poster at the San Antonio Breast Cancer Symposium (SABCS) here.

The drug, which has long been regarded as having no interaction with tamoxifen, "should be used with caution, especially in women with endoxifen concentrations that are known to be low," he said.

The issue of drug interactions with CYP2D6 has been controversial, commented Hiltrud Brauch, DPhil, of the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology in Stuttgart, Germany, who was not part of the study, but who moderated the SABCS poster discussion session.

Brauch was the leader of a study that reported in 2009 that variations in CYP2D6 have an effect on disease-free and event-free survival in patients taking tamoxifen.

"Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers," she said. "The long and the short of it is that this matters to women."

But as well as natural variation, several drugs -- including many of the antidepressants -- are known to either block CYP2D6 permanently or interfere with it while they are being taken, she noted.

For that reason, Brauch said, the study by Goetz and colleagues is important, suggesting that clinicians should be careful when they prescribe venlafaxine to women taking tamoxifen.

The study itself looked at paired blood samples from 30 women, taken before starting venlafaxine and 8 to 16 weeks afterward.

Across all genetic subgroups, Goetz reported, the drug depressed levels of endoxifen over time by a median of about 1.6 ng/ml (P=0.04).

On the other hand, it's still not known how much endoxifen is needed to provide a benefit, so that the effect of venlafaxine on breast cancer outcomes remains an open question.

Goetz said limited evidence suggests that at least 6 ng/ml is needed, and in the study, three women with low CYP2D6 activity saw their levels drop below that.

"The bottom line is that there is a decrease – it's small but it's statistically significant," he said. "The question really is: Are there subgroups of patients in which this is important?"

He and colleagues are currently conducting a phase I study to examine the question of optimal endoxifen levels and a phase II study will begin next year, he reported.

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