FlaxSeed Lignan for Breast Cancer Chemoprevention

描述（由申请人提供）：目的是在患乳腺癌的高风险女性中进行一项原理验证研究，评估在亚麻籽中发现的高水平天然木脂素的效果。木酚素的来源是市售产品Brevail（200 mg），其始终提供50 mg开环异落叶松树脂酚二糖苷（SDG）和流行病学研究中与乳腺癌风险降低相关的血清肠内酯水平。我们将评估与乳腺癌风险增加相关的几种生物标志物，包括通过随机乳晕周围细针穿刺（FNA）获得的增生性导管上皮细胞增殖、乳腺摄影乳腺密度、基线和Brevail治疗12个月后胰岛素样生长因子I（IGF-1）及其结合蛋白IGFBP-3的血清水平。这些风险生物标志物的变化将与血清肠内酯和肠二醇水平的变化相关。预计将有50名在FNA上具有足够细胞产量并且具有至少2%的Ki-67染色阳性细胞的绝经前女性入组本初步研究。研究目的包括估计：1）表达增殖抗原Ki-67的良性上皮细胞比例的变化; 2）乳腺摄影密度的变化; 3）血清IGF-1/IGFBP-3的变化;和4）血清SDG、肠内酯和肠二醇水平的测量以及与风险生物标志物调节的相关性。本研究将估计这些风险生物标志物在12个月内的变化幅度，这将为未来更大规模的安慰剂对照随机试验的样本量计算提供基础。这项研究将提供初步的证据，是否绝经前妇女在乳腺癌的高风险可能受益于木脂素，如果血清肠内酯水平维持在34 nM以上。如果是阳性的，这项研究的结果将是关键的设计和实施安慰剂对照的第二阶段预防试验与Brevail和/或商业亚麻籽。

DESCRIPTION (provided by applicant): The objective is to perform a proof of principle study in women at high risk for development of breast cancer, evaluating the effects of a natural lignan found in high levels in flaxseed. The source of lignan will be the commercial product Brevail (200 mg) which consistently provides the 50 mg of secoisolariciresinol diglycoside (SDG) and resultant serum enterolactone levels associated with reduction in breast cancer risk in epidemiologic studies. We will evaluate several biomarkers associated with increased risk for breast cancer including proliferation in hyperplastic ductal epithelium obtained by random periareolar fine needle aspiration (FNA), mammographic breast density, serum levels of insulin-like growth factor I (IGF-1) and its binding protein IGFBP-3, at baseline and after 12 months of Brevail. Change in these risk biomarkers will be correlated with change in serum enterolactone and enterodiol levels. It is anticipated that 50 pre-menopausal women with an adequate yield of cells on FNA and having at least 2% of cells that stain positive for Ki-67 will be enrolled in this pilot study. Study aims to be investigated include estimation of: 1) change in proportion of benign epithelial cells expressing the proliferation antigen Ki-67; 2) change in mammographic density; 3) change in serum IGF-1/IGFBP-3; and 4) measurement of serum SDG, enterolactone, and enterodiol levels and correlation with modulation of risk biomarkers. This study will provide an estimate of the magnitude of change over 12 months for these risk biomarkers, which will provide a basis for sample size calculation for a larger placebo controlled randomized trial in the future. This study will provide preliminary evidence as to whether premenopausal women at high risk for breast cancer are likely to benefit from lignans if serum enterolactone levels are maintained above 34 nM. If positive, the results of this study will be critical to the design and implementation of a placebo-controlled Phase II prevention trial with Brevail and/or commercial flaxseed.