Biomarker modulation/COX-2 inhibitor/Breast Cancer

描述（由申请人提供）乳腺癌仍然是一个主要的健康问题，尽管在早期发现和治疗的改进努力。目前的研究重点是预防乳腺癌。在这项研究中，一项关于他莫昔芬的大型III期化学预防试验显示，雌激素受体（ER）阳性乳腺癌的发病率降低。但是，他莫昔芬对ER阴性乳腺癌的发展没有影响。因此，除了他莫昔芬以外，还需要非激素类药物用于乳腺癌的化学预防。此外，目前还没有有效的替代生物标志物用于预防乳腺癌。最后，在第二阶段化学预防干预期间，需要开发比核心活检或细针抽吸（FNA）侵入性更小的乳腺组织采集方法。近年来，环氧合酶2（考克斯-2）在乳腺癌和早期乳腺病变中的表达被发现。塞来昔布是一种选择性考克斯-2抑制剂，具有抗增殖和促凋亡的特性。此外，最近显示导管灌洗是从乳腺组织获得导管上皮细胞的可行方法。我们的目标是以试点方式测试乳腺癌高危女性乳腺组织中塞来昔布对生物标志物的调节作用，并开发一种侵入性较小的组织采集方法，用于未来II期化学预防干预。具体而言，首先，我们的目的是评估环氧化酶-2抑制剂（塞来昔布）诱导的乳腺癌高危女性乳腺组织细胞学异常的调节，以及增殖（ki-67，ER，考克斯-2，Her-2/neu，EGFR，p53）和凋亡标志物（bcl-2，15-LOX）的调节。第二，我们的目的是比较乳腺上皮细胞产量和细胞学检查获得的标本，通过FNA与导管灌洗，并测试的可行性评估生物标志物导管灌洗液中获得的乳腺癌高危妇女的乳腺组织中使用未来的化学预防干预措施。40例高危女性（既往乳腺癌史或小叶原位癌史或估计5年Gail风险> 1.67）将接受基线导管灌洗和随机FNA，以分析细胞学异常和上述标志物。然后，女性将接受塞来昔布400 mg/天BID口服治疗6个月，之后将重复导管灌洗和FNA进行相同的标志物分析。Ki-67和其他增殖标志物的降低、细胞凋亡标志物的增加和细胞凋亡的逆转将为我们提供初步数据，以继续进行我们计划的塞来昔布II期安慰剂对照化学预防研究。最终，非激素化学预防剂的开发和替代标志物的鉴定将使我们能够计划以癌症发病率为终点的大规模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.