Biomarker-Based Phase IIB Trial of (Bazedoxifene-Conjugated Estrogen) to Reduce Risk for Breast Cancer

摘要 由于恐惧，很少有风险合格的妇女同意标准内分泌干预以降低乳腺癌风险 副作用与不完全疗效相结合，缺乏可靠的反应标志物。担心 血管扩张症状的开始或恶化是常见的障碍。组织选择性雌激素复合物 作为Duavee®销售的20 mg巴多昔芬（BZA）和0.45 mg结合雌激素（CE）被FDA批准用于 缓解潮热和预防骨质疏松症。Duavee®有望降低乳腺癌风险 考虑到雌激素拮抗剂在乳房和子宫中的作用，以及雌激素激动剂在骨中的特性。的 巴多昔芬成分不拮抗CE对血管炎症状的有利作用， 观察到该组合的肿瘤功效。在我们的试点中，对有症状的女性给予6个月的Duavee® 在乳腺癌风险增加的情况下， 乳腺摄影纤维腺体体积（Volpara™全自动评估），良性乳腺组织 增殖（Ki-67）和血清孕酮、IGF-1和生物可利用的睾酮。A阶段IIB多- 拟在血管紧张素转换酶高风险女性中进行一项为期6个月的Duavee®与安慰剂的机构试验 症状血液、乳房X光片和良性乳腺组织，以及拟人化和生活质量指标 将在基线时获得。受试者将按入组部位、纤维腺体体积和Ki-67分层;以及 随机分配至盲态Duavee®或匹配的安慰剂6个月，随后重复评估。的 主要终点是乳腺摄影纤维腺体体积的变化。次要终点为 乳腺良性组织Ki-67、雌孕激素受体蛋白、ER和PgR靶基因表达 （RT-qPCR）、血清IGF-1：IGFBP 3、生物可利用激素、可溶性核受体激活剂比率 因子κ B配体（sRANKL）对骨保护素的影响，以及患者报告的与 血管痉挛症状、生活质量和认知。进行反相蛋白质阵列和RNA-seq 以帮助阐明作用机制。BZA水平，体脂， 将检查内脏脂肪、胰岛素抵抗和炎性细胞因子对生物标志物调节的影响。 有利的生物标志物调节将提供Duavee®可能降低乳腺癌风险的证据 并建立潜在的标志物来预测III期化学预防试验的反应。

ABSTRACT Few risk-eligible women agree to standard endocrine interventions for breast cancer risk reduction due to fear of side effects combined with incomplete efficacy and lack of a reliable marker of response. Worry about initiation or worsening vasomotor symptoms is a common barrier. The Tissue Selective Estrogen Complex of bazedoxifene (BZA) 20 mg and conjugated estrogen (CE) 0.45 mg marketed as Duavee® is FDA-approved for relief of hot flashes and prevention of osteoporosis. Duavee® is promising for breast cancer risk reduction given the estrogen antagonist effects in the breast and uterus, and estrogen agonist properties in bone. The bazedoxifene component does not antagonize CE's favorable effects on vasomotor symptoms despite anti- tumor efficacy observed for the combination. In our pilot, 6 months of Duavee® given to symptomatic women at increased risk for breast cancer alleviated hot flashes and favorably modulated risk biomarkers of mammographic fibroglandular volume (Volpara™ fully automated assessments), benign breast tissue proliferation (Ki-67), and serum progesterone, IGF-1, and bioavailable testosterone. A phase IIB multi- institutional trial of 6 months of Duavee® vs placebo is proposed in high-risk women with vasomotor symptoms. Blood, mammogram, and benign breast tissue, and anthropomorphic and quality of life measures will be obtained at baseline. Subjects will be stratified by enrollment site, fibroglandular volume, and Ki-67; and randomized to blinded Duavee® or matched placebo for 6 months, followed by repeat assessments. The primary endpoint is change in mammographic fibroglandular volume. Secondary endpoints are change in benign breast tissue Ki-67, estrogen and progesterone receptor protein, ER and PgR target gene expression (RT-qPCR), serum IGF-1: IGFBP3, bioavailable hormones, the ratio of soluble receptor activator of nuclear factor kappa-Β ligand (sRANKL) to osteoprotegerin, and patient reported outcome measures related to vasomotor symptoms, quality of life, and cognition. Reverse phase protein array and RNA-seq are performed on benign tissue to aid in elucidation of mechanisms of action. The possible influence of BZA levels, body fat, visceral fat, insulin resistance, and inflammatory cytokines on biomarker modulation will be examined. Favorable biomarker modulation would provide evidence that Duavee® is likely to reduce risk for breast cancer and establish potential markers to predict response in a Phase III chemoprevention trial.