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乳腺癌的主要原因。 妇女的发病率和死亡率以及预防是一个未得到满足的主要需求。非甾体抗 抗炎药（NSAIDs），包括阿司匹林（阿萨），是最广泛使用的药物之一 用于轻微疼痛和关节炎，并显示出抗肿瘤活性。根据流行病学数据， 低剂量阿萨正在研究用于预防乳腺癌的临床试验 复发我们以前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作为其治疗的一部分的绝经后女性中， 乳腺癌治疗在一项中期分析中，SUL显著降低了乳腺密度， 12个月后通过MRI与观察组、对照组进行比较。此外，SUL降低 二次谐波显微镜（SHG）检测乳腺组织胶原蛋白直线度 在显微镜下观察，这种变化与乳腺密度的降低显著相关。 额外的基于MRI的乳房脂肪组织成像表明，新型SUL效应与 对脂肪中的抗炎/抗肿瘤M2型巨噬细胞具有作用。SUL是一个独特的 具有环氧合酶（考克斯）和非考克斯活性的前药。由于独特的抗癌 SUL在临床前模型和临床试验中的活性，已经研究了二十多年 最近，FDA授予快速通道状态，与CPP-1X一起批准作为 一种用于家族性腺瘤性息肉病患者的化学预防剂。SUL的活动， 预防上皮癌的临床前模型支持乳腺中类似的抗癌作用。 我们的新数据将临床前研究结果扩展到对乳腺密度的影响; 乳腺癌的危险因素。在这里，我们建议遵循我们有希望的初步数据， SUL 150 mg BID、阿萨325 mg QD随机、开放标签3组研究的自然下一步 在乳腺发育风险增加的绝经后妇女中， 癌我们将检验以下假设，即150 mg BID持续12个月的SUL将显著 降低高危女性的乳腺密度，上级阿萨，更便宜，更容易获得， 也许更安全的NSAID。其次，将对配对乳腺活检（基线和6个月后）进行 用于检验SUL对乳腺密度的影响部分通过以下途径介导的假设： 乳腺组织胶原蛋白排列和胶原蛋白表达的影响， SHG和全组织载玻片基质辅助激光解吸电离（MALDI）-质谱 光谱法此外，我们将探讨SUL和阿萨对乳腺脂肪的影响，包括 新的假说认为，它们的作用部分是通过对乳腺巨噬细胞的活性介导的 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.