Abstract
Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.
Highlights
Introduction and ObjectiveTamoxifen is an endocrine drug that has significantly improved outcomes in hormone receptor positive breast cancer [1]
An alternative approach to validate the endoxifen-efficacy association would be to use existing data from large, prospective trials of adjuvant tamoxifen use to predict individual patient’s expected endoxifen concentration and test the association with long-term survival data. This strategy would be a vast improvement over previous attempts to use only CYP2D6 genotype that have failed to validate the association [54,55]
In this review we have provided evidence-based recommendations on how best to conduct analyses to determine the contribution of CYP2D6 and other genetic and clinical variables to endoxifen concentration
Summary
Tamoxifen is an endocrine drug that has significantly improved outcomes in hormone receptor positive breast cancer [1]. Many studies have investigated the association of tamoxifen treatment outcomes with CYP2D6 genotype, as a surrogate of endoxifen concentration (Figure 1). The rationale for tamoxifen treatment of hormone receptor positive breast cancer is to prevent transcription of ER-regulated genes involved in breast cancer differentiation, proliferation, and migration [12]. Tamoxifen’s mechanism of action involves binding the ligand binding pocket of the ER that promotes a conformational change preventing recruitment of coactivators and instead cause association with corepressors repressing transcriptional activity of the ER [13,14] This process takes place because tamoxifen has a higher affinity to the ER than does estradiol (E2), its natural ligand
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