Abstract PS07-08: Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk
Authors: Cook Katherine L. , Jenshcke Ramsey , Corleto Karen , Fabian Carol , Hursting Stephen , Kimler Bruce , Landrock Danilo , Giles Erin 
Published: May 2024

Abstract
Background:
Many women at high risk for breast cancer will not take tamoxifen or aromatase inhibitors for cancer prevention due to concern of side effects including hot flashes. Further, tamoxifen has detrimental metabolic effects in some overweight/obese women. Duavee®, a tissue-selective complex of bazedoxifene + conjugated estrogen, is FDA-approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects and potential for breast cancer risk reduction. In a single arm clinical trial, BZA+CE reduced Ki-67 and mammographic density (PMID: 31420361), and this combination is currently being assessed further in a Phase IIB trial of postmenopausal high risk women with vasomotor symptoms. Here, we examined the modifying effects of obesity on response to BZA+CE in a rodent model of obesity and breast cancer risk.
Methods:
Rats received carcinogen at 7-weeks of age to induce mammary tumors and were fed a high-fat diet (46% kcal fat) to promote obesity. Lean and obese rat were selected based on adiposity at 16 weeks. Separate cohorts of lean and obese ovary-intact or ovariectomized (OVX) rats were randomized to a daily dose of BZA+CE or placebo control for 8 weeks. We assessed tumor development throughout the study and end of study RNA from mammary glands was analysed by gene expression microarray (Affymetrix). We also analyzed body weight/composition, markers of metabolic health (circulating glucose, insulin, adiponectin), as well as changes in the gut microbiome (metagenomic sequencing on DNA isolated from baseline and end-of-study fecal samples) in response to BZA+CE.
Results:
BZA+CE improved metabolic health in both ovary intact and OVX rats, including reduced body weight and % body fat, particularly in the visceral regions. These effects were greater in obese rats compared to lean. BZA+CE reduced the number of large adipocytes and increased small (insulin sensitive) adipocytes in the mammary adipose, indicating benefical changes in local tumor microenvironment. We found no evidence that Duavee® promoted tumor development or growth in ovary-intact or OVX’d rats. Gene set enrichment analysis (GSEA) of microarray data showed enrichment of cell proliferation pathways in MG from obese rats and these same pathways were downregulated with BZA+CE, consistent with anti-cancer effects. Analysis of the microbiome found that BZA+CE increased proportional abudance of Odoribacter laneus in the gut, regardless of lean/obese or intact/OVX status. Previous studies have demonstrated that this bacterim improves glucose control and reduces inflammatory cytokines when administered to obese mice, suggesting a possible mechanistic link in this study.
Conclusions:
Unlike traditional SERMs that can have negative metabolic effects, BZA+CE improved whole body and mammary gland metabolic health and reduced expression of cell proliferation pathways, particularly in obese rats. Prelminary data suggest that changes in the gut microbiome could contribute, at least in part, to these effects. Together this supports BZA+CE (Duavee) as an agent with potential beneficial effects on breast cancer risk reduction and improvements in metabolic health in women with obesity. Further analyses will guide assessment of outcomes in an ongoing parallel clinical study in postmenopausal women at high risk for breast cancer.
Citation Format: Katherine L. Cook, Ramsey Jenshcke, Karen Corleto, Carol Fabian, Stephen Hursting, Bruce Kimler, Danilo Landrock, Erin Giles. Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-08.