Three-Arm randomized trial comparing the effect of aspirin, sulindac or no treatment control on breast density in patients with elevated breast cancer risk

项目摘要 尽管在早期发现和治疗方面取得了进展，但乳腺癌仍然是导致 妇女的发病率和死亡率以及预防是一项尚未得到满足的重大需求。非类固醇抗- 包括阿司匹林(ASA)在内的炎症剂(NSAID)是使用最广泛的药物之一 用于表现出抗肿瘤活性的轻微疼痛和关节炎。根据流行病学数据， 低剂量阿司匹林正在进行预防乳腺癌的临床试验 复发。我们之前被资助进行非甾体抗炎药舒林酸(Sul)的临床试验 在接受芳香酶抑制剂治疗的绝经后妇女中，150 mg Bid是其 乳腺癌护理。在一项中期分析中，SUL显著降低了确定的乳房密度 经MRI对比观察，对照组术后12个月。此外，Sul减少了 二次谐波显微镜(SHG)检测乳房组织中胶原蛋白的直度 显微镜下观察，这种变化与乳房密度的下降显著相关。 额外的基于MRI的乳腺脂肪组织成像表明新的SuL效应是一致的 对脂肪中M2型巨噬细胞的抗炎/抗肿瘤作用。苏尔是独一无二的 具有环氧合酶(COX)活性和非COX活性的前药物。因为独特的抗癌药物 在临床前模型和临床试验中的活性，SUL已经被研究了二十多年 最近被FDA与CPP-1X一起授予快速通道身份，以获得批准 一种用于家族性腺瘤性息肉病患者的化学预防药物。苏宁的活动 预防上皮癌的临床前模型支持乳房中类似的抗癌作用。 我们的新数据将临床前的发现扩展到对乳房密度的影响；这是一个既定的风险 乳腺癌的致病因素。在这里，我们建议在我们有希望的初步数据之后， Sul 150 mg Bid，ASA 325 mg，qd的随机开放标签3臂研究的自然下一步 绝经后乳房发育风险增加的女性没有治疗控制 癌症。我们将测试假设，在150毫克的出价12个月将显着 降低高危女性的乳房密度，并优于ASA，后者更便宜，更容易获得，而且 也许更安全的非甾体抗炎药。其次，配对的乳房活检(基线和6个月后)将是 用来检验SuL对乳房密度的影响部分是通过 高度创新对乳房组织胶原排列和胶原表达的影响 倍频和全组织载玻片基质辅助激光解吸电离(MALDI)-MS 光谱分析。此外，我们还将探讨SuL和ASA对乳房脂肪的影响，包括 新的假说认为它们的作用部分是通过对乳房巨噬细胞的活性来实现的 组织。

Project Abstract Despite advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality in women and prevention a major unmet need. Non-steroidal anti- inflammatory agents (NSAIDs), including aspirin (ASA), are among the most widely used drugs for minor pain and arthritis that demonstrate anti-tumor activity. Based on epidemiological data, low dose ASA is under investigation in clinical trials for the prevention of breast cancer recurrence. We were previously funded to perform a clinical trial of the NSAID, sulindac (SUL) at 150 mg BID, in postmenopausal women receiving aromatase inhibitor therapy as part of their breast cancer care. In an interim analysis, SUL significantly reduced breast density determined by MRI compared to an observation, control group after 12 months. Further, SUL reduced collagen straightness in breast tissue by second harmonic generation microscopy (SHG) microscopy and the change was significantly correlated with a decrease in breast density. Additional MRI based imaging of breast adipose tissue suggest novel SUL effects consistent with effects on anti-inflammatory/anti-tumor M2 type macrophages in adipose. SUL is a unique pro-drug with cyclooxygenase (COX) and non-COX activities. Because of unique anti-cancer activity in preclinical models and clinical trials, SUL has been studied for more than two decades and recently granted Fast Track Status by the FDA in combination with CPP-1X for approval as a chemoprevention agent for patients with familial adenomatous polyposis. Activity of SUL in preclinical models to prevent epithelial cancers support similar anti-cancer action in the breast. Our new data extend the preclinical findings to effects on breast density; an established risk factor for breast cancer. Here we propose to follow our promising preliminary data with the natural next step of a randomized, open label 3 arm study of SUL 150 mg BID, ASA 325 mg QD and no treatment control in postmenopausal women at increased risk of developing breast cancer. We will test the hypothesis that SUL at 150 mg BID for 12 months will significantly lower breast density in at-risk women and be superior to ASA, a cheaper, more accessible, and perhaps safer NSAID. Secondarily, paired breast biopsies (baseline and after 6 months) will be used to test the hypothesis that SUL effects on breast density are partly mediated through effects on breast tissue collagen alignment and collagen expression using highly innovative SHG and whole tissue slide matrix assisted laser desorption ionization (MALDI)-mass spectrometry. In addition, we will explore SUL and ASA effects on breast adipose including novel hypotheses that their action is in part mediated through activity on macrophages in breast tissue.