Biomarker modulation/COX-2 inhibitor/Breast Cancer

生物标志物调节/COX-2抑制剂/乳腺癌

• 批准号: 6655615
• 负责人: BANU K ARUN
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655615
• 关键词: apoptosis; biomarker; breast neoplasms; cancer risk; carcinogenesis; cell morphology; cell proliferation; chemoprevention; clinical research; clinical trial phase I; female; fine needle aspiration; fluorescent in situ hybridization; human subject; human therapy evaluation; immunocytochemistry; mammary epithelium; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; patient oriented research; prostaglandin endoperoxide synthase; prostaglandin inhibitors; terminal nick end labeling; women's health

DESCRIPTION (provided by applicant)Breast cancer continues to be a major health problem despite efforts in early detection and improvements in treatment. Current research focus is now on the prevention of breast cancer. In that effort, a large phase III chemoprevention trial of tamoxifen showed a reduced incidence of estrogen receptor (ER) positive breast cancer. But, tamoxifen had no impact on the development of ER negative breast cancers. Therefore, non-hormonal agents beside tamoxifen are needed for the chemoprevention of breast cancer. Furthermore, currently there are no validated surrogate biomarkers for the use of breast cancer prevention. Finally, less invasive methods than core biopsies or fine needle aspirations (FNA) need to be developed for breast tissue acquisition during phase II chemopreventive interventions. Recently, Cyclooxygenase 2 (COX-2) expression has been observed in breast cancer and early breast lesions. Celecoxib is a selective COX-2 inhibitor that has antiproliferative and proapoptotic properties. In addition, ductal lavage was recently shown to be a feasible way to obtain ductal epithelial cells from the breast tissue. Our goal is to test, in a pilot fashion, the modulation of biomarkers in response to celecoxib in breast tissue of women who are at high risk for breast cancer and to develop a less invasive tissue acquisition method for the future use of phase II chemopreventive interventions. Specifically, first, we aim to evaluate cyclooxygenase-2 inhibitor (celecoxib) induced modulation of cytologic atypia, and modulation of proliferation (ki-67, ER, COX-2, Her-2/neu, EGFR, p53) and apoptosis markers (bcl-2, 15-LOX) in breast tissue of women who are high risk to develop breast cancer. Second, we aim to compare breast epithelial cell yield and cytologic atypia in specimens obtained via FNA versus ductal lavage and test the feasibility of evaluating biomarkers in ductal lavage fluid obtained from breast tissue of women at high risk for breast cancer for the use of future chemopreventive interventions. Forty high-risk women (history of previous breast cancer or history of lobular carcinoma in situ or estimated 5 year Gail risk > 1.67) will undergo basline ductal lavage and random FNA for the analysis of cytologic atyipia and above-mentioned markers. Women then will be treated with celecoxib 400 mg/day BID per oral for 6 months, after which the ductal lavage and FNA will be repeated for the same marker analyses. Demonstration of a decrease in Ki-67 and other proliferation markers, increase in apopototic markers and reversal of atypia will provide us with preliminary data to proceed with our planned phase II, placebo controlled chemoprevention study with celecoxib. Ultimately, the development of non-hormonal chemoprevention agents, and identification of surrogate markers will allow us to plan large-scale, phase III chemoprevention studies with the endpoint of cancer incidence.

尽管在早期发现和治疗改善方面做出了努力，但描述（由申请人提供）仍然是一个主要的健康问题。目前的研究重点是现在预防乳腺癌。在这项工作中，他莫昔芬的一项大型III期化学预防试验显示，雌激素受体（ER）阳性乳腺癌的发生率降低。但是，他莫昔芬对ER负面乳腺癌的发展没有影响。因此，需要在他莫昔芬旁边的非荷尔蒙剂来进行乳腺癌的化学预防。此外，目前尚无对乳腺癌预防的替代生物标志物的验证。最后，在II期化学预防干预措施期间，需要开发出比核心活检或细针吸入（FNA）的侵入性方法（FNA）。最近，在乳腺癌和早期乳腺癌病变中观察到了环氧合酶2（COX-2）的表达。 Celecoxib是一种选择性COX-2抑制剂，具有抗增殖和促凋亡特性。此外，最近显示导管灌洗是从乳腺组织中获取导管上皮细胞的一种可行方法。我们的目标是以试验方式测试生物标志物对塞勒克昔布的调节，这些乳腺癌在乳腺癌高风险的乳房组织中，并开发出一种侵入性的组织获取方法，以便将来使用II期化学预防性干预措施。具体而言，首先，我们旨在评估环氧酶-2抑制剂（Celecoxib）诱导的细胞学异型调节以及增殖的调节（Ki-67，ER，Cox-2，Her-2/neu，egfr，egfr，p53）和细胞凋亡标志物（Bcl-2，15-lox，15-lox，lox，15-lox，15-lox）在乳腺癌中患有乳腺癌的癌症患者高。其次，我们的目的是比较通过FNA与导管灌洗获得的标本中乳腺上皮细胞的产量和细胞学上的亚型，并测试评估来自女性乳腺癌的导管灌洗液中生物标志物在高风险中获得的导管灌洗液中的可行性，用于乳腺癌对未来的化学疗法使用。四十名高危妇女（先前的乳腺癌病史或原位叶癌病史或估计5年的盖尔风险> 1.67）将经历巴line导管灌洗和随机FNA，以分析细胞学atyipia和上述标记物。然后，妇女将用塞来昔布治疗400 mg/day bid的每次口服6个月，然后将导管灌洗和FNA重复进行相同的标记分析。证明了KI-67和其他增殖标记，凋亡标记的增加以及非独立现代的逆转将为我们提供初步数据，以继续我们计划的II期，安慰剂控制化学预防研究。最终，非荷尔蒙化学预防剂的发展以及替代标记物的鉴定将使我们能够计划以癌症发病率的终点计划进行大规模的III期化学预防研究。