Selenium Chemoprevention: Benefits and Harms

摘要 随着对以患者为中心的结果研究和精准医学的兴趣增加， 临床试验中治疗效果异质性（HTE）已成为研究的关键领域。HTE是一个 评估干预措施在不同亚组之间的影响程度。来自审判的证据 补充硒的研究表明，这是一个关键领域的HTE的调查。到目前为止，三大 微量元素硒（Se）作为化学预防剂的临床试验已经完成。一是在 营养预防癌症（NPC）试验，参与者每天补充200 µg Se或 匹配的安慰剂，参与者中结直肠癌发病率统计学显著降低58 观察随机接受硒补充剂。接下来，硒和维生素E的结果 前列腺癌预防试验（SELECT）。迄今为止最大规模的硒预防癌症的试验， SELECT证明补充200 µg/d硒的男性患结直肠癌的风险没有降低 作为L-硒代蛋氨酸。我们最近完成了硒试验，这是第三个主要的临床试验， 用于化学预防。这是一项III期、随机、双盲、安慰剂对照临床试验， 1535名参与者接受200微克/天的硒作为硒化酵母或安慰剂，以确定硒是否 补充可降低结肠直肠腺瘤复发的风险。总体结直肠无差异 检测到干预组的腺瘤复发;然而，亚组分析显示， 治疗效果异质性（Heterogeneity of Treatment Effect，HTE）在基线时患有晚期腺瘤的参与者中， 与对照组相比， 安慰剂然而，2型糖尿病（T2 D）的发病率也有统计学显著增加。 老年参与者（>63岁）服用硒。这些结果确定了一个主要的研究差距， 需要识别可能导致HTE的个体特征，从而确定是否 硒的补充对人体有益或有害。这是一个特别及时的问题，因为 大约一半的美国成年人报告使用膳食补充剂。我们在此提议调查 可能影响与硒补充有关的个体结果的几个因素，包括1）遗传 背景; 2）脂溶性抗氧化剂的摄入量和血液浓度;以及3）Oxylipin谱响应 补硒。总之，我们认为硒在特定个体中的体内功效和毒性 可能受遗传背景、与抗氧化剂的相互作用和氧脂素代谢组学特征的影响。的 这项研究的结果将对公共卫生建议产生直接影响， 这些特征可能引起补硒对健康的有益或有害影响。

ABSTRACT With increased interest in patient-centered outcomes research and precision medicine, investigation of heterogeneity of treatment effect (HTE) in clinical trials has emerged as a key area of study. HTE is an assessment of the degree to which the impact of an intervention varies between subgroups. Evidence from trials of selenium supplementation indicates that this is a critical area for investigation of HTE. To date, three major clinical trials of the trace element selenium (Se) as a chemopreventive agent have been completed. First, in the Nutritional Prevention of Cancer (NPC) trial, participants were supplemented with 200 µg of Se per day or matching placebo, and a statistically significant 58% reduction in colorectal cancer incidence among participants randomized to receive the selenium supplement was observed. Next, the results of the Selenium and Vitamin E Prostate Cancer Prevention Trial (SELECT) were published. The largest trial to date of Se for cancer prevention, SELECT demonstrated no reduction in risk of colorectal cancer among men supplemented with 200 µg/d of Se as L-selenomethionine. We have recently completed the Selenium Trial, which was the third major clinical trial of Se for chemoprevention. This was a Phase III, randomized, double-blind, placebo-controlled clinical trial in which 1535 participants received 200 µg/d of Se as selenized yeast or placebo to ascertain whether Se supplementation reduced the risk of colorectal adenoma recurrence. No differences in overall colorectal adenoma recurrence by intervention group were detected; however, subgroup analyses revealed the presence of heterogeneity of treatment effect (HTE). Among participants who had an advanced adenoma at baseline, there was a statistically significant reduction in adenoma recurrence for those randomized to Se as compared to placebo. However, there was also a statistically significant increase in the incidence of type 2 diabetes (T2D) among older participants (>63 years) receiving selenium. These results identify a major research gap regarding the need for identification of individual characteristics that may contribute to HTE and thus determine whether Se supplementation elicits a beneficial or harmful effect. This is a particularly timely question given that approximately half of American adults report using dietary supplements. We propose herein to investigate several factors that may affect individual outcomes related to Se supplementation, including 1) Genetic background; 2) Intake and blood concentrations of fat-soluble antioxidants; and 3) Oxylipin profiles in response to Se supplementation. In summary, we contend that the in vivo efficacy and toxicity of Se in a given individual may be influenced by genetic background, interactions with antioxidants, and oxylipin metabolomic profiles. The findings of this study will have a direct impact on public health recommendations by identifying individual characteristics that may elicit either beneficial or harmful health effects of Se supplementation.