Abstract 5259: Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk
Authors: Jenschke Ramsey M. , Corleto Karen A. , Fabian Carol J. , Hursting Stephen D. , Kimler Bruce F. , Landrock Danilo , Mahmood Tara N. , Cook Katherine L. , Giles Erin D. 
Published: April 2023

Abstract
Background: The majority of women risk eligible for primary breast cancer prevention with tamoxifen or aromatase inhibitors refuse uptake due to concerns about side effects, especially vasomotor symptoms. Tamoxifen may also have detrimental metabolic effects in overweight/obese women. Duavee™, a complex of bazedoxifene (BZA) and conjugated estrogen (CE), is FDA approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects in ovariectomized animals and potential for breast cancer risk reduction. A single arm clinical trial found reduction in Ki-67 and mammographic density such that BZA+CE is being further evaluated in a Phase IIB trial of peri and early postmenopausal women with vasomotor symptoms who are at high risk for breast cancer. Here, in a companion study, we assessed the effect of BZA+ CE on metabolic health and cancer risk in a rat model of carcinogen induced ER+ tumors and high fat diet induced obesity.
Methods: Rats received 50 mg/kg N-methylnitrosourea at 7 weeks to increase mammary tumor risk and were fed a high fat diet (46% kcal fat) to promote obesity. At 16 weeks lean and obese rat were selected based on % body fat and were then randomized to 8 weeks of daily oral vehicle control or 3mg BZA + 0.07mg CE/kg body weight. Systemic metabolic variables were measured at 16 and 24 weeks, and RNA from mammary glands analyzed by gene expression microarray (Affymetrix).
Results: BZA+CE resulted in systemic as well as mammary changes indicative of improved metabolic health, including: reduction in total and visceral fat (p&lt;0.01), glucose (p&lt;0.05), cholesterol (p&lt;0.001), and triglycerides(p=0.08), as well as an increase in the adiponectin:leptin ratio (p&lt;0.01). BZA+CE vs control increased the ratio of small (insulin sensitive) to large adipocytes in the mammary gland. Gene set enrichment analysis (GSEA) showed BZA+CE downregulated proliferation-associated pathways which had been upregulated in obese rats, consistent with anti-cancer effects. Obese rats treated with BZA+CE also had upregulation of metabolic pathways, including adipocyte differentiation, fatty acid metabolism, and inflammatory response pathways.
Conclusions: Unlike tamoxifen, BZA+CE improved whole body and mammary gland metabolic health, particularly in obese rats. Transcriptional profiling and GSEA demonstrated a blunting of cell cycle and proliferation and enrichment of metabolic and immune-related pathways. Together this supports BZA+CE (Duavee) as an agent to be explored for breast cancer risk reduction in obese individuals.
Funding: This work was supported in part by P30 CA168524, R00 CA169430, and R25 CA203650.
Citation Format: Ramsey M. Jenschke, Karen A. Corleto, Carol J. Fabian, Stephen D. Hursting, Bruce F. Kimler, Danilo Landrock, Tara N. Mahmood, Katherine L. Cook, Erin D. Giles. Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5259.