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CYP2D6 Polymorphisms and Response to Tamoxifen

Breast cancer patients with genotypes corresponding to normal CYP2D6 enzyme activity achieved better outcomes than those with diminished or no activity.

Endoxifene, one of two active metabolites that mediate tamoxifen's therapeutic effects, is formed through the action of the CYP2D6 enzyme. Several polymorphisms of the CYP2D6 gene that influence the enzyme's activity and, therefore, endoxifene levels, have been indentified. However, studies designed to uncover the link between patient response to tamoxifen and CYP2D6 enzyme activity (or CYP2D6 genotype) have yielded inconsistent results, perhaps as a result of limited sample sizes. By generating a study of sufficient power, investigators from Germany and the U.S. attempted to more definitively evaluate tamoxifen efficacy in relation to patients' CYP2D6 genotypes.

Data were collected both retrospectively and prospectively in 1325 patients who were treated with tamoxifen for early-stage, hormone receptor–positive breast cancer. Based on previously defined genotype–phenotype relationships, researchers categorized patients' CYP2D6 enzyme activities as normal (46% of patients), reduced (48%), or absent (6%), depending on their CYP2D6 genotype. During median follow-up of 6.3 years, patients with genotypes corresponding to normal enzyme activity achieved longer time to recurrence (P<0.001), event-free survival (P<0.003), and disease-free survival (P<0.005) than those with reduced or absent CYP2D6 activity. Although the recurrence rates at 9 years for patients with normal, reduced, and absent enzyme activity were 14.9%, 20.9%, and 29.0%, respectively, no differences in overall survival were detected between groups.

In a final analysis, the investigators plotted a hypothetical survival curve using data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (JW Oncol Hematol Jan 22 2008) — which compared tamoxifen and an aromatase inhibitor (AI) as adjuvant breast cancer therapy — and found that patients treated with the AI had similar survival rates compared with those of patients in the present study who had normal CYP2D6 activity (and received tamoxifen).

Comment: AIs should still be considered the preferred treatment in postmenopausal women. If the expected toxicities from AIs are high or cost is an issue for a particular patient, oncologists might consider evaluation of the patient's CYP2D6 genotype to determine whether tamoxifen (available as a generic formulation) can be used without compromising outcome.

— Virginia Kaklamani, MD, DSc

Dr. Kaklamani is an Assistant Professor in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago.

Published in Journal Watch Oncology and Hematology October 27, 2009

Citation(s):

Schroth W et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 2009 Oct 7; 302:1429.

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