Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen

Abstract

Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5 mg/dl (13.5-33.5 mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and high-density lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.

Trial registration: ClinicalTrials.gov NCT00228930.

Figure 1

The distribution of serum cholesterol at baseline and after 4 months of tamoxifen. The plot shows the distribution of serum LDL-cholesterol at baseline and after 4 months of tamoxifen treatment in 176 breast cancer patients. The baseline distribution is shown in gray bars, whereas the black bar represents the distribution following 4 months of tamoxifen treatment. The percentage of patients is on the y axis and LDL concentration (mg/dl) is shown on the x axis. The LDL categories were selected arbitrarily and no test statistics were conducted.

Figure 2

Response of serum lipid particle to tamoxifen in premenopausal women according to ER-α XbaI genotype. (a) Total cholesterol, (b) triglycerides, (c) HDL-cholesterol, and (d) LDL-cholesterol. The bars show the mean change in serum lipid concentration (mg/dl), whereas the error bars are the SE of the means. The y axis indicates the direction of the change in lipid concentration. The number of subjects in each genotype group is in parentheses against each bar. *P-value for gene–dose effect.

Figure 3

Response of lipid concentration to tamoxifen in postmenopausal women according to ER-β (ESR2-02) polymorphism. (a) Total cholesterol, (b) triglycerides, (c) HDL-cholesterol, and (d) LDL-cholesterol. The bars show the mean change in serum lipid concentration (mg/dl), whereas the error bars are the SE of the means. The y axis indicates the direction and magnitude of the change in serum lipid concentration. The number of subjects in each genotype group is in parentheses against each bar. *P-value for gene–dose effect.