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

三臂随机试验比较阿司匹林、舒林酸或无治疗对照对乳腺癌风险升高患者乳腺密度的影响

• 批准号: 10263993
• 负责人: Alison T. STOPECK
• 金额: $ 56.72万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263993
• 关键词: Adipose tissue; Animal Model; Animals; Anti-Inflammatory Agents; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Arthritis; Aspirin; Biological Markers; Biopsy; Breast; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Cancer Risk Factor; Breast biopsy; Cancer Etiology; Carcinoma; Cell model; Cessation of life; Chemopreventive Agent; Clinical Trials; Collagen; Contralateral Breast; Control Groups; Core Biopsy; Data; Dinoprostone; Disease; Dose; Drug usage; Early Diagnosis; Early treatment; Epidemiology; Estradiol; Estrogen receptor positive; Familial Adenomatous Polyposis Syndrome; Funding; Generations; Grant; Image; Individual; Intervention; Investigation; Iron; Lasers; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Gland Parenchyma; Mass Spectrum Analysis; Measures; Mediating; Medical Care Costs; Methods; Microscopy; Minor; Morbidity - disease rate; Non-Steroidal Anti-Inflammatory Agents; PTGS2 gene; Pain; Patient Agents; Patients; Pharmaceutical Preparations; Postmenopause; Pre-Clinical Model; Prevention; Primary Prevention; Prodrugs; Prostaglandin Inhibition; Prostaglandin-Endoperoxide Synthase; Quality of life; Randomized; Research Priority; Risk; Slide; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Sulindac; Survivors; Testing; Tissues; Woman; anti-cancer; anticancer activity; antitumor effect; arm; base; breast density; breast imaging; cancer care; cancer chemoprevention; cancer recurrence; cyclooxygenase 2; epidemiologic data; group intervention; inhibitor therapy; innovation; interest; macrophage; malignant breast neoplasm; mortality; novel; open label; pre-clinical; prevent; primary endpoint; psychosocial; second harmonic; side effect; three-arm study; three-arm trial; treatment arm; trial comparing; tumor

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.

项目摘要 尽管早期发现和治疗方面取得了进步，但乳腺癌仍然是 妇女的发病率和死亡率和预防是主要的未满足需求。非甾体类抗 炎症剂（NSAID），包括阿司匹林（ASA），是使用最广泛的药物之一 对于表现出抗肿瘤活性的轻微疼痛和关节炎。基于流行病学数据， 低剂量ASA正在研究预防乳腺癌的临床试验 复发。以前，我们被资助用于进行NSAID Sulindac（SUL）的临床试验 在150 mg竞标中，在接受芳香酶抑制剂治疗的绝经后妇女中 乳腺癌护理。在临时分析中，SUL显着降低了乳房密度 与观察结果相比，由MRI在12个月后进行对照组。此外，SUL还原 通过第二次谐波生成显微镜（SHG）在乳房组织中的胶原蛋白直度 显微镜和变化与乳房密度降低显着相关。 乳腺脂肪组织的其他基于MRI的成像表明新型的SUL效应一致 对脂肪中抗炎/抗肿瘤M2型巨噬细胞的影响。 SUL是独特的 与环氧合酶（COX）和非cox活性的促毒物。由于独特的反癌 在临床前模型和临床试验中，SUL已研究了二十多年 最近，FDA与CPP-1X合并以批准为 一种针对家族性腺瘤性息肉病患者的化学预防剂。 sul in 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。既定风险 乳腺癌的因素。在这里，我们建议遵循我们有希望的初步数据 随机开放标签3 ARM研究SUL 150 mg BID的天然下一步，ASA 325 mg QD 绝经后妇女没有患乳房的风险增加的治疗控制 癌症。我们将测试以下假设，即150 mg出价的SUL将显着明显 高危女性的乳房密度降低，比ASA优越，便宜，更容易获得，并且 也许更安全的NSAID。其次，配对的乳房活检（基线和6个月后）将是 用于检验的假设，即SUL对乳腺密度的影响部分通过 使用高度创新的乳腺组织胶原蛋白对齐和胶原蛋白表达的影响 SHG和整个组织幻灯片矩阵辅助激光解吸电离（MALDI） - 质量 光谱法。此外，我们将探索SUL和ASA对乳腺脂肪的影响 新颖的假设是，它们的作用部分是通过对乳腺巨噬细胞的活性而介导的 组织。