Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment

Abstract

Objectives: Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations.

Patients and methods: Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates.

Results: In univariate analysis, higher activity of CYP2C8 (regression β=0.22, P=0.020) and CYP2C9 (β=0.20, P=0.04), lower body weight (β=-0.014, P<0.0001), and endoxifen measurement during winter (each β<-0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R by 1.3%.

Conclusion: Our results further support a minor contribution of CYP2C9 genetic variability toward steady-state endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

Figure 1. CONSORT Diagram of Patient Matriculation from Clinical Trial to this Pharmacogenetic Analysis

Of the 500 patients enrolled in the original clinical trial, 361 had evaluable endoxifen data, 355 had usable CYP2D6 genetic information, and 302 were successfully genotyped on the ADME PGx Pro Panel and were included in this analysis.

Figure 2. Endoxifen Concentration by CYP2C8, CYP2C9, and CYP2C19 Activity

Box and whisker plot (circles represent outliers) of steady-state endoxifen concentration stratified by predicted activity phenotype for CYP2C8 (left), CYP2C9 (middle), and CYP2C19 (right). Endoxifen concentration increased as predicted phenotypic activity increased for each gene (p=0.02, p=0.04, p=0.11, respectively).

Figure 3. Association of Endoxifen Concentration with Clinical Variables

Steady-state endoxifen concentration was associated with body weight and the season of sample collection. Figure 3 (left): Increased patient body weight (kg) was associated with lower endoxifen concentrations (β=−0.014, p<0.0001). Figure 3 (right): Endoxifen concentrations were lower in samples collected during fall (β=−0.55, p=0.0002) summer (β=−0.55, p=0.0009) and spring (β=−0.39, p=0.02) compared with those collected during winter.