Abstract P3-04-19: Inhibition of ER-positive breast cancer progression with duavee, a new form of hormone replacement therapy
Authors: Dembo AG , Aledort E , Greene GL 
Published: March 2017

Abstract
Menopause occurs in all women between the ages of 45 and 55 and often results in undesirable vasomotor symptoms. Hormone replacement therapy (HRT) can alleviate these symptoms, including hot flashes, difficulty sleeping, fatigue, and vaginal atrophy, and also prevents osteoporosis. PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, was found to increase the risk of breast cancer in the Women's Health Initiative (WHI) trial. Due to the perceived risk based largely on the results of the WHI trial, the number of women taking HRT has dramatically decreased. Studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a new form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. Importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. We are also studying the effects of CE+BZA on early mammary cancer progression in the polyoma middle T antigen (PyMT) transgenic mouse model, which is sensitive to estrogens. In addition, we are studying the effects of CE+BZA in an ERa-positive patient-derived xenograft (PDX) mouse model. We have determined that CE modulates gene expression in MCF7 cells similar to 17β-estradiol (E2), and that BZA is able to inhibit these effects. We have also observed that CE increases ERα occupancy, similar to E2, at response elements associated with some estrogen target genes, whereas CE+BZA decreases this occupancy. In the PyMT mouse model, CE+BZA delays the onset of mammary tumors in ovariectomized mice and prolongs their survival when compared to E2 and CE treatment alone. In the PDX model, the CE+BZA tumor growth curve is below vehicle, although it does not quite reach statistical significance. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT.
Citation Format: Dembo AG, Aledort E, Greene GL. Inhibition of ER-positive breast cancer progression with duavee, a new form of hormone replacement therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-19.