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

项目摘要 传统的激素替代疗法，曾经是治疗更年期症状的主要方法， 发现会显著增加患浸润性乳腺癌(IBC)的风险。这导致了一种新的 一类称为组织选择性雌激素复合体(TSECs)的化合物。这类特工中的第一个 结合结合雌激素(CE)(倍美力®)和巴多昔芬(BZA)，FDA批准CE/BZA在 治疗更年期症状和骨质疏松症的商标Duavee®。从那时起，一个实质性的 大量证据表明，CE/BZA可能对女性有额外的治疗益处。 人们普遍认为IBC的进展是通过上皮和间质两种机制发生的。最近进来的 体外和体内数据支持CE/BZA通过对导管的影响防止进展为IBC 乳腺上皮和微环境。在上皮细胞中，CE/BZA拮抗雌激素- 雌激素受体(ER-α)活性标志物的诱导增殖和表达并降解ER-α 蛋白。在基质中，CE/BZA增加清道夫受体CD36的表达，因此， 减少细胞外基质蛋白和促炎细胞因子的表达 有助于促进促癌微环境的发展。根据这些初步数据，我们 假设TSEC CE/BZA将在人类乳房中具有抗肿瘤作用。 作为IBC的非专性先兆，导管原位癌(DCIS)是检测我们的 假设。我们提出了一项随机安慰剂对照的机会窗试验，在140名患者中使用CE/BZA 绝经后妇女ER+DCIS。介入持续时间为手术前28±7天 切除，以使用诊断核心活检和手术样本来比较乳房CE/BZA。 首先，我们将评估CE/BZA对上皮细胞的影响，重点是增殖和调节 ERα信令。其次，我们将监测与进展相关的上皮和间质信号。最后， 我们将进一步研究CE/BZA在女性DCIS患者中的毒性和耐受性。我们将利用这两个标准 和多重免疫组织化学检测生物标记物的表达。两者的全局表达分析 将进行上皮和基质检查，以确定新的ER依赖信号和药物基因组学 将进行分析，以确定可能影响BZA代谢的多态。最终验证的质量 生活质量调查问卷将用于评估女性DCIS患者对CE/BZA的耐受性。结果将是 诊断活检标本与手术切除标本的比较及CE/BZA的对比 安慰剂组。我们的最终目标是为被诊断为DCIS的绝经后妇女提供一种新颖和 安全的治疗选择，以防止进展为IBC。

Project Summary 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 estrogen- induced 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.