Evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ

Traditional hormone replacement therapy, once the mainstay for treatment of menopausal symptoms, was found to significantly increase the risk of invasive breast cancer (IBC). This led to the development of a new class of compounds called Tissue Selective Estrogen Complexes (TSECs). The first of this class of agents combines conjugated estrogens (CE) (Premarin®) and bazedoxifene (BZA), The FDA approved CE/BZA under the trademark DUAVEE® for treatment of menopausal symptoms and osteoporosis. Since then, a substantial body of evidence has emerged suggesting that CE/BZA may have additional therapeutic benefits in women. It is widely accepted that progression to IBC occurs through both epithelial and stromal mechanisms. Recent in vitro and in vivo data provide support that CE/BZA prevents progression to IBC through its effects on the ductal epithelium and microenvironment of the mammary gland. In epithelial cells, CE/BZA antagonizes estrogeninduced proliferation and expression of markers of Estrogen Receptor (ERα) activity and also degrades ERα protein. In the stroma, CE/BZA increases expression of the scavenger receptor CD36 and, consequently, reduces expression of extracellular matrix proteins and pro-inflammatory cytokines that have been shown to contribute to the development of pro-tumorigenic microenvironment. Based on these preliminary data, we hypothesize that the TSEC CE/BZA will have an anti-tumorigenic effect in the human breast. As a non-obligate precursor to IBC, ductal carcinoma in situ (DCIS) constitutes an ideal disease state to test our hypothesis. We propose a randomized placebo controlled window of opportunity trial with CE/BZA in 140 postmenopausal women with ER + DCIS. The duration of intervention will be for 28 ± 7 days prior to surgical resection to enable comparison of CE/BZA on the breast using the diagnostic core biopsy and surgical sample. First, we will evaluate the effect of CE/BZA on epithelial cells with an emphasis on proliferation and modulation of ERα signaling. Second, we will monitor epithelial and stromal signatures associated with progression. Lastly, we will further characterize toxicity and tolerability of CE/BZA in women with DCIS. We will utilize both standard and multiplex immunohistochemistry to measure biomarker expression. Global expression profiling of both the epithelium and stroma will be performed to identify novel ER dependent signatures and pharmacogenomic analysis will be conducted identify polymorphisms that could affect metabolism of BZA. Finally validated quality of life questionnaires will be administered to assess tolerability of CE/BZA in women with DCIS. Results will be compared between diagnostic biopsy and surgical resection specimens and contrasted between the CE/BZA and placebo group. Our ultimate goal is to provide postmenopausal women diagnosed with DCIS a novel and safe therapeutic option to prevent progression to IBC.