Abstract
BackgroundWhile 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.FindingsIn 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-52) contains supplementary material, which is available to authorized users.
Highlights
In vitro and in vivo studies have strongly suggested that tamoxifen activity is mainly due to endoxifen and that the concentration of this active metabolite is in part controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results
This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy
Introduction in vitro and in vivo studies have strongly suggested that tamoxifen activity is mainly due to endoxifen and that the concentration of this active metabolite is in part controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results
Summary
In vitro and in vivo studies have strongly suggested that tamoxifen activity is mainly due to endoxifen and that the concentration of this active metabolite is in part controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results. Endoxifen plasma concentrations are highly variable among patients. In light of the possibility that multiple pathways control endoxifen plasma concentrations, and given that the pharmacogenetic studies so far reported are not consistent, it is likely that the absolute endoxifen concentrations better predict tamoxifen activity in patients. 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
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