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CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer

Richard R Love*, Zuerenesay Desta, David Flockhart, Todd Skaar, Evan T Ogburn, Anuradha Ramamoorthy, Gemma B Uy, Adriano V Laudico, Nguyen Van Dinh, Le Hong Quang, Ta Van To, Gregory S Young, Erinn Hade and David Jarjoura

Author Affiliations

International Breast Cancer Research Foundation, 505 S Rosa Rd Ste 35E, Madison, WI 53719, USA

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SpringerPlus 2013, 2:52  doi:10.1186/2193-1801-2-52

Published: 15 February 2013

Abstract

Background

While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results.

Findings

In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case–control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease.

We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control.

Conclusions

This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.