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手段， 发现显著增加浸润性乳腺癌（IBC）的风险。这导致了一个新的发展 这类化合物称为组织选择性雌激素复合物（TSEC）。这类特工中的第一个 结合结合雌激素（CE）（倍美力®）和苯多昔芬（BZA），FDA批准CE/BZA， 商标DUAVEE®用于治疗更年期症状和骨质疏松症。从那时起，大量 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，发展到IBC是通过上皮和基质机制发生的。中最近 体外和体内数据支持CE/BZA通过其对导管的作用防止进展为IBC。 乳腺的上皮和微环境。在上皮细胞中，CE/BZA拮抗雌激素- 诱导雌激素受体（ERα）活性标记物的增殖和表达，并降解ERα 蛋白在基质中，CE/BZA增加清道夫受体CD 36的表达，因此， 减少细胞外基质蛋白和促炎细胞因子的表达， 有助于促肿瘤发生微环境的发展。根据这些初步数据，我们 假设TSEC CE/BZA在人乳腺中具有抗肿瘤作用。 作为IBC的非专性前体，导管原位癌（DCIS）构成了检测我们的 假说.我们提出了一个随机安慰剂对照的机会窗口试验与CE/BZA在140 ER + DCIS的绝经后女性。手术前干预持续时间为28 ± 7天 切除，以便能够使用诊断性芯活检和手术样本比较乳腺上的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信号其次，我们将监测与进展相关的上皮和间质特征。最后， 我们将进一步描述CE/BZA在DCIS女性中的毒性和耐受性。我们将使用两种标准 和多重免疫组织化学以测量生物标志物表达。两种基因的全局表达谱分析 将进行上皮和间质，以鉴定新的ER依赖性特征和药物基因组学特征。 将进行分析以鉴定可能影响BZA代谢的多态性。最终验证质量 将进行生存期问卷调查，以评估CE/BZA在DCIS女性中的耐受性。结果将 比较诊断性活检和手术切除标本，并对比CE/BZA 安慰剂组。我们的最终目标是为诊断为DCIS的绝经后妇女提供一种新的， 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.