A Prospective, Randomized Study to Compare Effects of Ulipristal Acetate with a Combined Oral Contraceptive on Breast Epithelial Cell Proliferation.

 描述(申请人提供)：乳腺癌几乎占所有女性癌症的四分之一。据估计，2014年美国有超过23万名女性被诊断出患有这种疾病，其中4万人死于这种疾病。他莫昔芬是一种有效的化学预防药物；然而，它并没有被广泛使用，部分原因是它增加了子宫内膜癌和静脉血栓栓塞症的风险。美国预防服务工作组建议只对乳腺癌高危人群使用他莫昔芬。迫切需要为高风险和中等风险妇女开发可接受的预防该疾病的方法。这项拟议的研究是一项针对18-40岁绝经前妇女的临床试验，旨在评估每日服用Ulipristal Acetate(UPA)抑制乳腺上皮细胞增殖的能力，并与雌激素和孕激素口服避孕药(COC)的效果进行比较。UPA是一种选择性孕激素受体调节剂(SPRM)，最长可用作12个月的每日药物，用于治疗子宫肌瘤引起的月经过多，目前正在美国进行试验，以评估其作为每日避孕药的用途。这项拟议的研究将使我们能够调查uPA是否有可能减少乳腺细胞的增殖，如果长期使用，可能会降低乳腺癌的风险。我们将比较治疗3个月末两组(uPA和COC)的乳腺细胞增殖，通过乳腺活检中Ki67的表达来衡量。我们还将比较两组的变化。之所以将uPA的效果与传统的COC进行比较，是因为uPA可能被用作日常避孕药。乳腺中的细胞增殖发生在整个月经周期中，在周期的黄体期(孕激素升高期)大约是黄体期的两倍。荷尔蒙对乳房的作用是迅速的，一种抗孕激素，如uPA，将阻断乳房中黄体酮的作用，预计会迅速降低绝经前女性的乳房细胞增殖。尿激酶型纤溶酶原激活剂对子宫内膜的影响仍在继续研究，并且令人放心。目前还没有发现使用COC可以降低乳腺细胞的增殖，也与乳腺癌风险的任何降低无关。乳房细胞增殖的变化也将与乳房MRI上看到的变化进行比较。如果这些都高度相关，未来的研究将能够在不需要乳房活检的情况下完成。

 DESCRIPTION (provided by applicant): Breast cancer accounts for almost a quarter of all cancers in women. It is estimated that in the U.S. in 2014 more than 230,000 women were diagnosed with the disease and 40,000 died of the disease. Tamoxifen is an effective chemopreventive agent; however, it is not widely used, in part due to its increased risks of endometrial cancer and venous thromboembolism. The United States Preventive Services Task Force recommends tamoxifen use only for those at high risk of breast cancer. There is an urgent need to develop acceptable means of preventing the disease both for high risk and average risk women. The proposed study is a clinical trial in premenopausal women aged 18-40 to evaluate the capacity of daily Ulipristal Acetate (UPA) to reduce breast epithelial cell proliferation and to measure its effect compared to that found with a combined estrogen-progestin oral contraceptive (COC). UPA is a selective progesterone receptor modulator (SPRM) in use as daily medication up to 12 months for the treatment of menorrhagia due to uterine fibroids, and is currently in trials in the U.S. to evaluate its use as a daily contraceptie. The proposed study will allow us to investigate the potential of UPA to reduce breast cell proliferation and possibly breast cancer risk if used over an extended period of time. We will compare breast cell proliferation, as measured by Ki67 expression in breast biopsies, at the end of 3 months treatment to baseline values in the 2 groups (UPA and COC). We will also compare the changes in the 2 groups to each other. The comparison of the effect of UPA to that of a conventional COC is because of UPA's potential use as a daily contraceptive. Cell proliferation in the breast occurs throughout the menstrual cycle and is roughly twice as high in the luteal phase (elevated progesterone phase) of the cycle. The actions of hormones on the breast are rapid and an anti-progestin such as UPA, which will block the action of progesterone in the breast would be predicted to quickly lower breast cell proliferation in premenopausal women. Effects of UPA on the endometrium continue to be studied and are reassuring. COC use has not been found to lower breast cell proliferation and is not associated with any decrease in risk of breast cancer. The changes in breast cell proliferation will also be compared to changes seen on breast MRI. If these are highly correlated future studies will be able to be done without the need for breast biopsies.