Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer

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.

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

“…The final step in the metabolic pathway from tamoxifen to endoxifen is the hydroxylation of NDtam to endoxifen [29,30]. Our results agree with the extensive prior literature [12] that patients with greater CYP2D6 activity have higher steady-state endoxifen concentrations. Several studies have reported an association between CYP2C9/19 and endoxifen levels [12]; however, this association was not identified in our analyses.…”

“…These inconsistent findings may be partially due to the contribution of other active metabolites, such as 4OHtam [11,[21][22][23], which has also been reported to affect treatment efficacy [3,4], and perhaps other, less active metabolites such as Z-4 -endoxifen and Z-4 -OHtam [7]. As is described in detail in our recent review [12], substantial work has been carried out to identify the genetic variables associated with endoxifen concentrations, but much less work has been conducted to identify the genetic variants that affect non-endoxifen metabolites. To investigate the genes associated with the tamoxifen metabolism pathway, which could facilitate further study of the efficacy of individualized tamoxifen treatment, we conducted an assessment of the effect of genetic variation in 20 pharmacogenes on steady-state concentrations of tamoxifen and its metabolites.…”

“…The gene encoding CYP2D6 is highly polymorphic, with over 100 allelic variants/haplotypes known, including several common variants associated with reduced or abolished CYP2D6 phenotypic activity [10]. The CYP2D6 genotype explains up to 50% of endoxifen variability and around 9% of 4OHtam variability [11]; thus, there are additional factors contributing to the formation of these two active metabolites [12]. Tamoxifen metabolism is complex and involves several other genes that may be predictive of endoxifen and 4OHtam concentrations, including CYP2Cs, CYP3As, SULTs, and UGTs [12].…”

“…The CYP2D6 genotype explains up to 50% of endoxifen variability and around 9% of 4OHtam variability [11]; thus, there are additional factors contributing to the formation of these two active metabolites [12]. Tamoxifen metabolism is complex and involves several other genes that may be predictive of endoxifen and 4OHtam concentrations, including CYP2Cs, CYP3As, SULTs, and UGTs [12]. The generation of active metabolites may require multiple metabolic steps for which genes responsible for upstream metabolism may affect concentrations of the downstream active metabolite.…”

“…It was previously reported that CYP2B6 and CYP2D6 contribute to the formation of Z-4 -OHtam, but the genes associated with Z-4 -endoxifen remain unknown [11]. Few in-vivo studies on breast cancer patients using tamoxifen have investigated the genetic variables that affect non-endoxifen metabolites, as was recently reviewed by our group [12]. The objective of this study was to elucidate the effect of variation in 20 pharmacogenes on concentrations of tamoxifen and seven of its metabolites, measured by a gold-standard LCMSMS methodology.…”