FlaxSeed Lignan for Breast Cancer Chemoprevention

描述（由申请人提供）：目的是在乳腺癌高风险女性中进行原理证明研究，评估亚麻籽中发现的高水平天然木脂素的影响。木脂素的来源将是商业产品Brevail（200毫克），在流行病学研究中，Brevail持续提供50毫克的第二异构体脂醇二糖苷（SDG）和由此产生的血清肠内酯水平与降低乳腺癌风险相关。我们将评估与乳腺癌风险增加相关的几个生物标志物，包括随机乳泡周围细针抽吸（FNA）获得的增生导管上皮的增殖，乳房x线摄影乳腺密度，胰岛素样生长因子I （IGF-1）及其结合蛋白IGFBP-3在基线和12个月后的血清水平。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名绝经前妇女参加这项初步研究，这些妇女在FNA上有足够的细胞产量，并且至少有2%的细胞染色为Ki-67阳性。研究目的包括：1)表达增殖抗原Ki-67的良性上皮细胞比例的变化；2) x线密度变化；3)血清IGF-1/IGFBP-3的变化；4)血清SDG、肠内酯和肠二醇水平的测定及其与风险生物标志物调节的相关性。该研究将提供这些风险生物标志物在12个月内变化幅度的估计，这将为未来更大的安慰剂对照随机试验的样本量计算提供基础。如果血清肠内酯水平维持在34 nM以上，该研究将为绝经前乳腺癌高风险妇女是否可能受益于木脂素提供初步证据。如果结果是积极的，那么这项研究的结果将对Brevail和/或商业亚麻籽的安慰剂对照II期预防试验的设计和实施至关重要。

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.