Abstract PD3-06: Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer
Authors: Fabian Carol J , Nye Lauren , Phillips Teresa A , Winblad Onalisa , Zalles Carola M , Hagan Christy R , Goodman Merit L , Gajewski Byron J , Koestler Devin C , Chalise Prabhakar , Kimler Bruce F 
Published: March 2020

Abstract
Agents which both reduce risk for development of breast cancer and relieve vasomotor symptoms are likely to have good uptake and adherence. 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 biomarkers. Risk biomarkers for postmenopausal breast cancer included fully automated mammographic volumetric density (Volpara®), benign breast tissue Ki-67, and serum levels of progesterone, IGF-1 and IGFBP3, bioavailable estradiol and testosterone. Exploratory biomarkers included selected estrogen and progesterone responsive gene expression in benign breast tissue. 28 peri- and post-menopausal women at increased risk for breast cancer were enrolled; 13 in Cohort A with baseline Ki-67 &lt; 1% and 15 in Cohort B with baseline Ki-67 of 1-4%. All completed the study with &gt; 85% drug adherence. 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&lt; 0.001). Significant changes in risk 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&lt;0.01); and for women from Cohort B, a reduction in Ki-67 (p=0.017) despite an increase in serum bioavailable estradiol. Unsupervised cluster analysis of RT-qPCR results indicated two clusters with differences in change in early estrogen response genes including ERS1, TFF1, GREB1a, PGR and AREG. The 10 women in one cluster tended to have increased expression of two or more of early estrogen response genes, but not increased expression of CCND1 (cyclin D1) or genes downstream of activated progesterone receptor such as STAT5a, PdK4, and STK. A trend towards decrease in several genes with predominant stromal expression implicated in breast cancer development including FASN, LEP, CXCL12, SDF1a and B, and CYP19A1 was observed. The 17 women in cluster 2 by contrast exhibited predominately decreased expression of early estrogen response genes. Given the favorable effects on vasomotor symptoms and risk biomarkers, a placebo-controlled Phase IIB trial is warranted.
This study was supported in part by grants from the Breast Cancer Research Foundation (BCRF-16-049, BCRF-17-049, BCRF-18-049); and an NIH Clinical and Translational Science Award grant (UL1 TR000001, formerly UL1RR033179) awarded to the University of Kansas Medical Center, and an internal clinical pilot grant program of the KUMC Research Institute.
Citation Format: Carol J Fabian, Lauren Nye, Teresa A Phillips, Onalisa Winblad, Carola M Zalles, Christy R Hagan, Merit L Goodman, Byron J Gajewski, Devin C Koestler, Prabhakar Chalise, Bruce F Kimler. Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-06.