Biomarker modulation/COX-2 inhibitor/Breast Cancer

描述（由申请人提供）尽管在早期发现和改善治疗方面作出了努力，但乳腺癌仍然是一个主要的健康问题。目前的研究重点是预防乳腺癌。在这项研究中，一项大型的他莫昔芬III期化学预防试验显示，它能降低雌激素受体（ER）阳性乳腺癌的发病率。但是，他莫昔芬对雌激素受体阴性乳腺癌的发展没有影响。因此，除他莫昔芬外，还需要非激素药物来进行乳腺癌的化学预防。此外，目前还没有经过验证的替代生物标志物用于乳腺癌预防。最后，在II期化学预防干预期间，需要开发比核心活检或细针穿刺（FNA）侵入性更小的方法来获取乳房组织。近年来，环氧化酶2 （COX-2）在乳腺癌和早期乳腺病变中表达。塞来昔布是一种选择性COX-2抑制剂，具有抗增殖和促凋亡特性。此外，导管灌洗最近被证明是从乳腺组织中获得导管上皮细胞的可行方法。我们的目标是以试点的方式测试生物标志物对塞来昔布在乳腺癌高风险妇女乳腺组织中的调节作用，并为未来II期化学预防干预的使用开发一种侵入性较小的组织获取方法。具体来说，首先，我们的目标是评估环氧化酶-2抑制剂（塞来昔布）诱导的细胞异型性调节，以及乳腺癌高风险女性乳腺组织中增殖（ki-67， ER, COX-2, Her-2/neu， EGFR, p53）和凋亡标志物（bcl-2, 15-LOX）的调节。其次，我们的目标是比较通过FNA和导管灌洗获得的乳腺上皮细胞产量和细胞学异型性，并测试评估乳腺癌高风险女性乳腺组织导管灌洗液中生物标志物的可行性，以用于未来的化学预防干预。40名高危妇女（既往有乳腺癌病史或小叶原位癌病史或估计5年Gail风险bbb1.67）将接受基线导管灌洗和随机FNA，以分析细胞学不典型和上述标志物。然后，女性将接受塞来昔布400mg /天/次口服BID治疗，持续6个月，之后将重复进行导管灌洗和FNA，以进行相同的标志物分析。Ki-67和其他增殖标记物的减少、凋亡标记物的增加和非典型性逆转的证明将为我们计划中的塞来昔布二期安慰剂对照化学预防研究提供初步数据。最终，非激素化学预防剂的开发和替代标记物的鉴定将使我们能够计划大规模的以癌症发病率为终点的III期化学预防研究。

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.