二甲双胍降低肥胖相关乳腺癌风险的II期研究：一项随机对照试验方案
Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.
作者信息
Martinez Jessica A, Chalasani Pavani, Thomson Cynthia A, Roe Denise, Altbach Maria, Galons Jean-Philippe, Stopeck Alison, Thompson Patricia A, Villa-Guillen Diana Evelyn, Chow H-H Sherry
机构信息
The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.
Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA.
出版信息
BMC Cancer. 2016 Jul 19;16:500. doi: 10.1186/s12885-016-2551-3.
BACKGROUND
Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.
METHODS/DESIGN: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.
DISCUSSION
The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.
背景
美国三分之二的成年女性超重或肥胖。高体重指数（BMI）和成年后体重增加是包括绝经后乳腺癌在内的多种慢性疾病的危险因素。BMI升高的女性绝经后乳腺癌风险较高，这可能归因于相关的代谢紊乱，包括循环性激素和脂肪因子改变、促炎细胞因子升高以及胰岛素抵抗。二甲双胍是一种广泛使用的抗糖尿病药物，已证明对代谢紊乱有有益作用，因此可能降低肥胖女性患乳腺癌的风险。此外，二甲双胍的抗增殖作用表明它可能降低乳腺密度，乳腺密度是公认的乳腺癌风险生物标志物。
方法/设计：这是一项针对有代谢综合征因素的超重/肥胖绝经前女性的二甲双胍II期随机、双盲、安慰剂对照试验。符合条件的参与者将被随机分为接受二甲双胍850毫克每日两次（n = 75）或安慰剂（n = 75），为期12个月。主要终点是基于磁共振成像（MRI）获取的脂肪-水特征的乳腺密度变化。次要结局包括血清胰岛素水平、血清胰岛素样生长因子（IGF）-1与胰岛素样生长因子结合蛋白（IGFBP）-3比值、血清IGF-2水平、血清睾酮水平、血清瘦素与脂联素比值、体重和腰围的变化。探索性结局包括血浆和乳头抽吸液中代谢组学谱的变化。还将探索在一组参与者中收集的乳腺组织的组织结构以及细胞和分子靶点的变化。
讨论
该研究将评估二甲双胍是否能导致乳腺密度、选定的蛋白质和激素、身体代谢产物以及体重和组成发生有益变化。该研究应有助于确定二甲双胍在不断增加的多种疾病风险人群中潜在的乳腺癌预防活性。
试验注册
ClinicalTrials.gov标识符：NCT02028221。于2014年1月2日注册。资助编号：1R01CA172444-01A1，于2013年9月11日授予。
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