Exploring Effects of Weight Loss on Ductal Carcinoma In Situ

描述（由申请人提供）：肥胖是绝经后发生的浸润性乳腺癌的已知危险因素。肥胖妇女死于乳腺癌的频率也是正常体重妇女的两倍。许多临床前研究表明，限制热量对动物癌症进展有好处-但是，在人类中会看到类似的效果吗？为了响应转化研究的呼吁，将确定生物/生物行为途径，通过减肥可能会影响癌症预后（PAR-12-229），我们提出了一个试点研究，建立在我们成功的术前干预，以回答研究问题，“负能量平衡伴随体重减轻是否会对肿瘤生物学和宿主环境产生抗癌作用？“我们将随机分配40名超重或肥胖的绝经后妇女，诊断为导管原位癌（DCIS），（浸润性癌症的前兆）选择乳房切除术或肿块切除术的患者：1）注意力控制组，其接受关于饮食方法的指导以纠正营养缺乏和针对受影响乳房同侧手臂的渐进式阻力训练（PRT）;或2实验组，将接受PRT和指导以纠正营养缺乏加上强化干预以通过饮食、锻炼和行为改变促进1.5-2磅/周的体重减轻。本研究将探索和对比从实验组与注意力控制组的入组到手术时观察到的体重指数（BMI）变化，并监测能量摄入和体力活动的变化。将研究这些变化与以下终点的关系：a）与癌症进展、激素状态、炎症和其他能量相关因素相关的选定循环生物标志物和基因表达的变化; B）肿瘤增殖和凋亡的速率; c）肿瘤标志物，例如，胰岛素受体、VEGF、AKT、NFkB和与激素、炎症和能量额定因子（CHIEF）途径的会聚相关的磷蛋白;和d）功能和健康相关结果。由于肿瘤组织和血液都将从干预前到干预后进行检查，因此这项研究将提供令人兴奋的新数据，可以阐明能量平衡影响乳腺癌从非侵入性发展到侵入性状态的途径。虽然超重和肥胖的乳腺癌幸存者建议长期减肥，但目前尚不清楚将身体置于负能量平衡状态是否会对肿瘤产生有利影响。如果肿瘤生物学和宿主环境的有益变化发生在短期的术前体重减轻中，则本研究提供了概念证据，即体重减轻可以提供可接受的补充治疗选择，可以与长期管理的积极监测相结合。因此，提出的研究不仅将增加我们对负能量平衡对肿瘤生物学影响的理解，而且可以改变护理标准，并为每年被诊断患有DCIS的5万名美国女性提供更保守的治疗选择。

DESCRIPTION (provided by applicant): Obesity is a known risk factor for invasive breast cancers that occur post-menopause. Obese women also die twice as frequently from breast cancer than those of normal weight. Numerous preclinical studies show the benefits of caloric restriction on cancer progression in animals - but, will similar effects be seen in humans? In response to a call for translational studies that will identify biological/biobehavioral pathways through which weight loss may affect cancer prognosis (PAR-12-229), we propose a pilot study that builds on our success of pre-surgical interventions to answer the research question, "does negative energy balance with concomitant weight loss invoke anti-cancer effects on tumor biology and the host environment?" We will randomly assign 40 overweight or obese postmenopausal women diagnosed with ductal carcinoma in situ (DCIS) (a precursor to invasive cancer) who elect mastectomy or lumpectomy to 1-of-2 study arms: 1) an Attention Control Group that receives instruction on dietary approaches to correct nutritional deficiencies and progressive resistance training (PRT) that targets the arm ipsilateral to the affected breast; or 2 an Experimental Group that will receive PRT and guidance to correct nutritional deficiencies plus an intensive intervention to promote a 1.5-2 pound/week weight loss through diet, exercise, and behavior modification. This study will explore and contrast changes in body mass index (BMI) observed from enrollment to the time of surgery in the experimental vs. attention control arms, and also monitor changes in energy intake and physical activity. These changes will be studied in relation to the following endpoints: a) changes in select circulating biomarkers and gene expression related to cancer progression, hormonal status, inflammation and other energy-related factors; b) rates of tumor proliferation and apoptosis; c) tumor markers, e.g., insulin receptor, VEGF, AKT, NFkB, and phosphoproteins associated with the Convergence of Hormones, Inflammation and Energy-Rated Factors (CHIEF) pathway; and d) functional and health-related outcomes. Because both tumor tissue and blood will be examined from pre-to-post-intervention, this study will provide exciting new data that can elucidate pathways by which energy balance affects breast cancer progression from a non-invasive to an invasive state. Although longer term weight loss is recommended for overweight and obese breast cancer survivors, it is not known whether placing the body in a state of negative energy balance will have a favorable impact on the tumor. If beneficial changes in tumor biology and the host environment occur with short-term, pre-surgical weight loss, this study provides proof of concept that weight loss may offer an acceptable and complementary treatment option that could be combined with active surveillance for longer term management. Thus, the research that is proposed will not only increase our understanding of the impact of negative energy balance on tumor biology, but could change the standard of care and offer a more conservative treatment option for the 50,000 American women who are diagnosed with DCIS each year.