Obesity-Related Mechanisms and Mortality in Breast Cancer Survivors

本研究的目的是探讨超重/肥胖、绝经后乳腺癌存活者对生活方式干预或两者兼而有之的干预程度，以降低乳腺癌死亡率。我们将使用“Biomarker Bridge”设计，通过Biomarker风险评分，将乳腺癌幸存者队列的临床结果与随机对照试验的中期结果联系起来。 生物标记物风险评分发展：我们将分析375份存档血样中相互关联的生物标记物的组合，这些血样来自有乳腺癌病史的绝经后妇女(125例[乳腺癌死亡]：250名匹配对照)。这些生物标志物代表了肥胖与绝经后乳腺癌相关的已提出的机制：(1)胰岛素-胰岛素样生长因子轴的改变，(2)内源性性激素浓度，以及(3)慢性炎症。我们将使用条件Logistic回归找出一组最能预测乳腺癌死亡率的标记物 对预后因素进行调整的模型。该模型(即，生物标记物风险分数)测量由于联合生物标记物浓度而导致的疾病风险的对数赔率。因此，这一风险评分可以衡量个体中由于这些标记物的变化而导致的对数赔率的变化，并将用于评估二甲双胍和生活方式干预随机试验的临床影响。二甲双胍/生活方式干预试验：我们将对340例超重/肥胖、绝经后乳腺癌进行为期6个月的随机对照试验 幸存者。参与者将被随机分为(1)安慰剂、(2)二甲双胍、(3)生活方式干预和安慰剂、或(4)生活方式干预和二甲双胍。生活方式干预将重点减少能量摄入和增加能量消耗，以实现7%的体重减轻。构成风险评分的生物标记物将在基线和6个月时采集的空腹血液样本中进行检测。 每个干预措施改变(例如，降低)Biomarker风险分数的程度将用于预测乳腺癌死亡率的变化(例如，降低)。我们假设，二甲双胍和生活方式干预将降低乳腺癌死亡率，这些干预措施的组合将对降低NSK产生相加的效果。总而言之，这种生物标记桥设计将(I)形成生物标记风险 (Ii)检查二甲双胍/生活方式干预如何改变这一风险得分，以及(Iii)从而评估二甲双胍和生活方式干预对将肥胖与乳腺癌死亡率联系起来的生物过程的影响程度。

Ttie objective of ttiis proposed study is to investigate ttie degree to wtiichi nnetfornnin, a lifestyle intervention, or both, can reduce breast cancer mortality among overweiqtit/obese, postmenopausal breast cancer survivors. We will use a "Biomarker Bridge" design that links clinical outcomes from a breast cancer survivor cohort with intermediate outcomes from a randomized controlled trial by means of a Biomarker Risk Score. Biomarker Risk Score Development: We will assay panels of interrelated biomarkers in 375 archived blood samples obtained from oven/veight/obese, postmenopausal women with a history of breast cancer (125 cases [breast cancer death]:250 matched controls). These Biomarkers represent proposed mechanisms by which obesity is associated with postmenopausal breast cancer: (1) alterations in the insulin-IGF axis, (2) concentrations of endogenous sex hormones, and (3) chronic inflammation. We will identify a set of markers that best predicts breast cancer mortality using conditional logistic regression models adjusted for prognostic factors. This model (i.e., Biomarker Risk Score) measures the log-odds of disease risk due to joint biomarker concentrations. Therefore this Risk Score can measure changes in log-odds due to changes in these markers in an individual and will be used to assess the clinical impact of the metformin and lifestyle intervention randomized trial. Metformin/Lifestyle Intervention Trial: We will conduct a 6-month, randomized controlled trial in 340 overweight/obese, postmenopausal breast cancer survivors. Participants will be randomized in equal numbers to (1) placebo, (2) metformin, (3) lifestyle intervention and placebo, or (4) lifestyle intervention and metformin. The lifestyle intervention will focus on reducing energy intake and increasing energy expenditure to achieve a 7% weight reduction. Biomarkers that compose the Risk Score will be assayed in fasting blood samples collected at baseline and 6 months. The degree to which each intervention changes (e.g., reduces) the Biomarker Risk Score will be used to predict changes (e.g., reductions) in breast cancer mortality. We hypothesize that metformin and lifestyle interventions will reduce breast cancer mortality and that the combination of those interventions will have an additive effect on lowering nsk. In summary, this Biomarker Bridge Design will (i) develop a Biomarker Risk Score that predicts breast cancer mortality, (ii) examine how a metformin/lifestyle intervention changes this Risk Score, and (iii) thereby assess the degree to which metformin and lifestyle interventions influence the biological processes linking obesity with breast cancer mortality.