GNRH AGONIST REGIMEN FOR BREAST CANCER PREVENTION

描述：（申请人的描述） 该计划的目标是开发一种每日透粘膜药物产品 用于绝经前妇女，由促性腺激素释放激素组成 激动剂地洛瑞林（D），部分替代雌二醇（E2）， 睾酮（T）。 低剂量的补充E2使血清水平 雌激素低于月经周期中的任何时候。 加回剂量 T的计算只是为了取代卵巢T的生产被阻断， GnRHA的作用。 激素药物产品是专为 乳腺癌高危女性的BRCA1长期治疗 突变 长期目标是实现（并通过随机 试验）大大降低了这些妇女患乳腺癌的风险， 增强（并通过随机试验证明）绝经前 在这些妇女中进行乳房X光筛查， 密度，从而提高灵敏度和特异性， 绝经前乳房X光检查 假设乳腺癌风险降低的科学基础 包括已知的乳腺癌风险的降低， 卵巢切除术后性类固醇水平降低。 这些减少性类固醇 水平导致乳腺上皮细胞有丝分裂活性降低。 减少 这种由口服药物引起的子宫内膜上皮细胞有丝分裂活动 避孕药已经多次被证明会导致非常显著的 长期降低患子宫内膜癌的风险。 这表明 减少相关的细胞增殖可能会产生深远的影响， 降低风险。 乳腺细胞增殖减少的早期迹象 应该是降低乳房X线摄影的密度。 第一个具体的 该研究的目的是证明乳腺摄影密度的降低 我们目前的鼻内药物 第二个具体目标是 证明了E2加T可以预防以下症状和体征： 雌激素分泌不足 这项为期12个月的研究旨在开发25名受试者的经验， 确认试验方法，包括减少乳房X光检查 密度 这将是一项多中心单剂量水平研究。 将在基线、6和12小时后定量乳腺摄影密度 治疗12个月后和停止研究12个月后。 控件将为 相似的年龄，乳腺癌家族史和BRCA1突变。 将以设盲的客观方式进行乳腺摄影密度测量 因此，这种非随机对照应足以 确定任何方案诱导的减少的统计学显著性 乳腺摄影密度，本研究的主要目的。

DESCRIPTION: (Applicant's Description) The goal of this program is to develop a daily trans-mucosal drug product for premenopausal women consisting of the gonadotropin-releasing hormone agonist deslorelin (D), with partial replacement of estradiol (E2) and testosterone (T). The low dose of add-back E2 gives serum levels of estrogen lower than at any time in the menstrual cycle. The add-back dose of T is calculated to just replace the ovarian T production blocked by the action of the GnRHA. The hormonal drug product is designed for the long-term treatment of women at high risk of breast cancer with a BRCA1 mutation. The long-term aim is to achieve (and demonstrate by randomized trial) substantially reduced breast cancer risk in these women, and to enhance (and demonstrate by randomized trial) the efficacy of premenopausal mammographic screening in these women by reducing their mammographic densities and hence improving the sensitivity and specificity of premenopausal mammography. The scientific basis of the hypothesized reduction in breast cancer risk includes the known reduction in breast cancer risk associated with the reduced sex-steroid levels after oophorectomy. These reduced sex-steroid levels lead to lower mitotic activity in breast epithelium. Reduction of such epithelial mitotic activity in the endometrium induced by oral contraceptives has been repeatedly demonstrated to lead to very significant long-term reduction in the risk of endometrial cancer. This demonstrates that reducing the relevant cell proliferation may produce profound reductions in risk. An early sign of reduced breast cell proliferation should be a reduction in mammographic densities. And, the first specific aim of the study is to demonstrate the reduction of mammographic densities with our current intranasal drug product. The second specific aim is to demonstrate that the add-back E2 plus T prevents signs and symptoms of hypoestrogenism. This 12-month study is designed to develop a 25 subject experience to confirm trial methodology, including the reduction of mammographic densities. This will be a multi-center single dose-level study. Mammographic densities will be quantitated at baseline, after 6 and 12 months of treatment and after 12 months off study. Controls will be of similar age, family history of breast cancer and BRCA1 mutations. Mammographic density measurements will be made in a masked objective manner and such non-randomized controls should, therefore, be adequate for establishing the statistical significance of any regimen-induced reduced mammographic densities, the primary aim of this study.