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

摘要 由于恐惧，很少有符合风险条件的女性同意标准的内分泌干预措施来降低乳腺癌风险 副作用与疗效不完全和缺乏可靠的反应标志相结合。担心 血管舒缩症状的开始或恶化是常见的障碍。丹参的组织选择性雌激素复合体 Bazedoxifene(BZA)20 mg和结合雌激素(CE)0.45 mg以Duavee®的名称上市，经FDA批准用于 缓解潮热，预防骨质疏松。Duavee®有望降低乳腺癌风险 鉴于雌激素在乳房和子宫中的拮抗作用，以及在骨骼中的雌激素激动剂特性。这个 Bazedoxifen组分不能拮抗CE对血管舒缩症状的有利作用 观察联合用药的肿瘤疗效。在我们的试点中，有症状的女性服用6个月的Duavee® 乳腺癌风险增加缓解潮热和有利调节的风险生物标记物 乳房钼靶纤维腺体积(VOLPARA™全自动评估)，良性乳腺组织 增殖指数(Ki-67)、血清孕酮、胰岛素样生长因子-1和生物可利用睾酮。A阶段IIB多- 建议对患有血管舒张剂的高危女性进行为期6个月的Duavee®与安慰剂的机构试验 症状。血液、乳房X光和良性乳腺组织，以及拟人化和生活质量测量 将在基线时获得。受试者将根据登记地点、纤维腺体积和Ki-67进行分层； 随机服用Duavee®或与之匹配的安慰剂，为期6个月，然后重复评估。这个 主要终点是乳房X光检查纤维腺体体积的改变。次要端点在中更改 乳腺良性组织Ki-67、雌孕激素受体蛋白、ER和PGR靶基因的表达 (RT-qPCR)、血清IGF-1：IGFBP3、生物可利用激素、可溶性核受体激活剂比率 因子kappa-Β配体(SRANKL)与护骨素的关系以及患者报告的与 血管舒缩症状、生活质量和认知。进行反相蛋白质阵列和rna-seq 有助于阐明其作用机制。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记物的调节作用。 有利的生物标记物调节将提供Duavee®可能降低乳腺癌风险的证据 并建立潜在的标记物来预测第三阶段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.