FlaxSeed Lignan for Breast Cancer Chemoprevention

描述(由申请人提供)：目的是对患乳腺癌的高危女性进行一项原则证明研究，评估在亚麻籽中发现的高水平天然木脂素的效果。木脂素的来源将是商业产品Brevail(200毫克)，它在流行病学研究中持续提供与降低乳腺癌风险有关的50毫克第二异落叶松脂醇二苷(SDG)和由此产生的血清肠内酯水平。我们将评估几个与乳腺癌风险增加相关的生物标志物，包括通过乳晕周围细针抽吸(FNA)获得的增生性导管上皮的增殖、乳房X线摄影、血清胰岛素样生长因子I(IGF-1)及其结合蛋白IGFBP-3的水平，在基线和Brevail服药12个月后。这些危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Ki-67染色阳性。研究的目的包括：1)良性上皮细胞表达增殖抗原Ki-67的比例的变化；2)钼靶摄影密度的变化；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危险生物标志物调控的相关性。这项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证据，表明如果血清肠内酯水平保持在34 NM以上，乳腺癌高危绝经前妇女是否可能受益于木脂素。如果是肯定的，这项研究的结果将对设计和实施使用Brevail和/或商业亚麻籽的安慰剂对照第二阶段预防试验至关重要。

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.