Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse

A B Sanchez-Spitman, J J Swen, V O Dezentjé, D J A R Moes, H Gelderblom, H J Guchelaar, A B Sanchez-Spitman, J J Swen, V O Dezentjé, D J A R Moes, H Gelderblom, H J Guchelaar

Abstract

CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C19*2 and CYP2C19*17 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan-Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17). Only significant differences (p value < 0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value < 0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Tamoxifen metabolism.
Figure 2
Figure 2
Association of CYP2C19 genotypes with tamoxifen (A), 4-hydroxy-tamoxifen (B), and NDM-tamoxifen (C) and endoxifen (D) concentration levels. The CYP2C19 genotypes presented are: CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17.
Figure 3
Figure 3
Kaplan–Meier curve for RFS by CYP2C19 genotypes. Log-rank test p value: 0.898. RFS Relapse-free survival.
Figure 4
Figure 4
Classification Tree analyses for endoxifen concentrations and CYP2D6 predicted phenotypes. EM extensive metabolizer, hetEM heterogenous extensive metabolizer, IM intermediate metabolizer, N number of individuals, PM poor metabolizer, SD standard deviation, UM ultrarapid metabolizer.

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Source: PubMed

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