Obesity-Related Mechanisms and Mortality in Breast Cancer Survivors

本研究的目的是调查减肥、生活方式干预或两者结合在何种程度上可以降低超重/肥胖绝经后乳腺癌幸存者的乳腺癌死亡率。我们将使用“生物标志物桥”设计，通过生物标志物风险评分将乳腺癌幸存者队列的临床结局与随机对照试验的中间结局联系起来。 生物标志物风险评分开发：我们将在375份存档的血液样本中检测相关生物标志物组，这些血液样本来自有乳腺癌病史的绝经后女性（125例[乳腺癌死亡]：250例匹配对照）。这些生物标志物代表了肥胖与绝经后乳腺癌相关的拟议机制：（1）胰岛素-IGF轴的改变，（2）内源性性激素的浓度，和（3）慢性炎症。我们将使用条件Logistic回归确定一组最能预测乳腺癌死亡率的标志物 模型调整预后因素。该模型（即，生物标志物风险评分）测量由于联合生物标志物浓度引起的疾病风险的对数几率。因此，该风险评分可以测量个体中这些标志物变化引起的对数比值变化，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。代谢/生活方式干预试验：我们将在340例超重/肥胖的绝经后乳腺癌患者中进行一项为期6个月的随机对照试验。 幸存者受试者将以相同数量随机分配至（1）安慰剂组，（2）二甲双胍组，（3）生活方式干预和安慰剂组，或（4）生活方式干预和二甲双胍组。生活方式干预将侧重于减少能量摄入和增加能量消耗，以实现7%的体重减轻。将在基线和6个月时采集的空腹血液样本中分析构成风险评分的生物标志物。 每个干预的变化程度（例如，降低）生物标志物风险评分将用于预测变化（例如，降低）乳腺癌死亡率。我们假设二甲双胍和生活方式干预将降低乳腺癌死亡率，并且这些干预的组合将对降低nsk产生叠加效应。总之，该生物标志物桥设计将（i）开发生物标志物风险 预测乳腺癌死亡率的评分，（ii）检查二甲双胍/生活方式干预如何改变该风险评分，（iii）从而评估二甲双胍和生活方式干预影响肥胖与乳腺癌死亡率相关的生物学过程的程度。

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.