Selenium Colorectal Cancer Chemoprevention Trials

描述(申请人提供)：结直肠腺瘤(CRA)是大多数结直肠癌(CRC)的良性先兆，结直肠癌是导致癌症死亡的主要原因；晚期CRA是最有可能进展为CRC的。虽然大多数CRA可以在结肠镜检查中取出，但在3-5年后再次接受结肠镜检查的患者中，有20%-50%的人出现了异时性的CRA，即新的CRA。此外，部分癌不能通过筛查结肠镜检查来预防，因此有必要采取其他预防策略，如化学预防。作为补充剂，硒(Se)是一种微量的饮食矿物质，被结合到专门的硒蛋白中，此前在一项非黑色素瘤皮肤癌化学预防试验中显示，作为次要终点，硒可以预防CRC和流行的CRA。可以在随机对照试验(RCT)中对CRC的化学预防药物进行评估，比较干预组和安慰剂组之间的异时性CRA发生率与FDA认定为CRC替代品的CRA的效果结果。目前还没有关于补充硒作为结直肠癌化学预防或任何其他癌前疾病作为主要终点的随机对照试验的报道。这项申请为期3年，用于完成硒试验(SET)；一项随机对照试验，每天200 5g硒酵母，随机化完成。主要的研究假设是，用硒酵母治疗3到5年将减少异时性CRA的发生率，而不会出现相关的严重毒性。请拨资金，以便在2014年初完成对所有1800名参与者的研究，并用于数据分析和报告。增加了一项主要的新研究目的，以解决最近发表的研究中提出的过量硒暴露可能增加患2型糖尿病(T2D)风险的建议。虽然人类与硒相关的T2D的机制尚不清楚，但动物研究表明，谷胱甘肽过氧化物酶1(GPX1)的长期激活可能导致高胰岛素血症、高血糖、胰岛素抵抗和肥胖。因此，补充Se是否有助于T2D的问题具有重要的公共卫生意义。在SET队列中，我们提出了两种方法来研究Se对T2D以及胰岛素敏感性和分泌的影响：使用整个队列的流行病学方法；以及在300名受试者(150名服用安慰剂，150名服用硒酵母)的子队列中，使用改良的口服葡萄糖耐量试验在个体水平上评估补硒对胰岛素分泌和敏感性的影响。在二次分析中，我们将调查基线硒水平、遗传背景和/或小剂量阿司匹林的使用是否会改变硒对CRA发生或T2D风险的影响。 公共卫生相关性：硒试验的积极结果将提供明确的证据，支持补充硒的作用，如硒酵母，在预防CRC中的作用。此外，这项研究将严格解决目前尚未解决的问题，即补充硒可能会增加糖尿病前期变化和T2D的风险。考虑硒的基线水平、阿司匹林的使用和硒蛋白基因的遗传变异将有助于了解可能影响个体受益和/或对硒不良影响的敏感性的因素。

DESCRIPTION (provided by applicant): Colorectal adenomas (CRAs) are the benign precursors of most cases of colorectal cancer (CRC), a leading cause of cancer deaths; advanced CRAs are those most likely to progress to CRC. Although most CRAs can be removed at colonoscopy, 20-50% of individuals undergoing repeat colonoscopy 3-5 years later have metachronous, i.e. new, CRAs. Furthermore, a proportion of CRCs are not preventable through screening colonoscopy, necessitating alternative preventive strategies, such as chemoprevention. When given as a supplement, selenium (Se), a trace dietary mineral that is incorporated into specialized selenoproteins was previously shown to protect against CRC and prevalent CRAs as secondary endpoints in a non-melanoma skin cancer chemoprevention trial. Chemopreventive agents for CRC can be assessed in randomized controlled trials (RCTs) comparing metachronous CRA rates between intervention and placebo groups with results of effects on CRA recognized by the FDA as a CRC surrogate. No RCTs of Se supplements for CRC chemoprevention or for any other preneoplastic condition as the primary endpoint, have been reported. This application is for 3 years funding to complete The Selenium Trial (SeT); an RCT of Se, 200 5g daily as selenized yeast, for which randomization is completed. The primary study hypothesis is that treatment with Se yeast for 3 to 5 years will reduce the rate of metachronous CRAs without associated serious toxicities. Funding is requested to follow remaining SeT participants through study completion for all 1,800 participants in early 2014, and for data analysis and reporting. A major new study aim has been added to address the suggestion in recent published studies that excessive Se exposure may increase risk for type 2 diabetes (T2D). Although a mechanism for Se-related T2D in human is obscure, animal studies suggest that chronic activation of glutathione peroxidase 1 (GPX1), a potent anti-oxidant selenoprotein, may lead to the development of hyperinsulinemia, hyperglycemia, insulin resistance, and obesity. Therefore, the question of whether or not Se supplementation contributes to T2D has important public health implications. In the SeT cohort, we propose two approaches to studying the effects of Se on T2D, and insulin sensitivity and secretion: an epidemiological approach using the entire cohort; and assessment of the effect of Se supplementation on insulin secretion and sensitivity at the individual level using a modified oral glucose tolerance test in a sub- cohort of 300 subjects (150 on placebo and 150 on Se yeast). In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D. PUBLIC HEALTH RELEVANCE: A positive outcome in The Selenium Trial would contribute unequivocal evidence in favor of a role for Se supplementation, as Se yeast, in CRC prevention. In addition, this study will rigorously address currently unresolved concerns that Se supplementation may increase risk for pre-diabetic changes and T2D. Consideration of baseline levels of Se, aspirin use, and genetic variation in selenoprotein genes will help to inform on factors that may influence individual benefit and/or sensitivity to adverse effects of Se.