Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

Abstract

Interventions that relieve vasomotor symptoms while reducing risk for breast cancer would likely improve uptake of chemoprevention for perimenopausal and postmenopausal women. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg; Duavee) to assess feasibility and effects on risk biomarkers for postmenopausal breast cancer. Risk biomarkers included fully automated mammographic volumetric density (Volpara), benign breast tissue Ki-67 (MIB-1 immunochemistry), and serum levels of progesterone, IGF-1, and IGFBP3, bioavailable estradiol and testosterone. Twenty-eight perimenopausal and postmenopausal women at increased risk for breast cancer were enrolled: 13 in cohort A with baseline Ki-67 < 1% and 15 in cohort B with baseline Ki-67 of 1% to 4%. All completed the study with > 85% drug adherence. Significant changes in biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (P = 0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (P < 0.01), an increase in serum bioavailable estradiol (P < 0.001), and for women from cohort B a reduction in Ki-67 (P = 0.017). An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause-specific quality-of-life total, vasomotor, and sexual domain scores were also observed (P < 0.001). Given the favorable effects on risk biomarkers and patient reported outcomes, a placebo-controlled phase IIB trial is warranted.

Figure 1:

Percentage of breast epithelial cells acquired by RPFNA that stained immunocytochemically positive for Ki-67 at baseline and after a 6 month intervention with Duavee®. Comparison of change by non-parametric Wilcoxon test.

Figure 2:

Heatmap demonstrating the results of unsupervised clustering analysis of PCR data. For individual subjects, an increase in gene expression is indicated by red and a decrease in gene expression is indicated by green The 27 subjects with paired specimens are separated into two clusters (Cluster 1, n=10 and Cluster 2, n=17), primarily on the basis of alterations in the estrogen early response genes PGR, GREB1, ESR1, AREG, and TFF1.

Figure 3:

Distribution of change in mammographic total fibroglandular volume assessed by Volpara software for subjects on the Duavee® pilot study and age-matched controls with two mammograms separated by 6–12 months.