Exploring Effects of Weight Loss on Ductal Carcinoma In Situ

描述(申请人提供)：肥胖是绝经后发生浸润性乳腺癌的已知危险因素。肥胖女性死于乳腺癌的几率也是正常体重女性的两倍。大量临床前研究表明，限制卡路里对动物癌症进展的好处--但是，类似的效果会在人类身上看到吗？为了响应一项转化性研究的号召，即确定体重减轻可能影响癌症预后的生物/生物行为途径(PAR-12-229)，我们提议进行一项先导性研究，该研究建立在我们手术前干预成功的基础上，以回答这样一个研究问题：“负能量平衡与伴随的体重减轻是否会对肿瘤生物学和宿主环境产生抗癌效果？”我们将随机分配40名被诊断患有乳腺原位癌(DCIS)(浸润性癌症的先兆)的超重或肥胖绝经后女性，她们选择乳房切除术或肿块切除术，并接受1/2研究臂：1)注意力控制组，接受纠正营养不足的饮食方法指导和针对受影响乳房同侧手臂的渐进性抵抗力训练(PRT)；或2试验组，将接受PRT和纠正营养缺乏的指导，以及通过饮食、运动和行为调整促进1.5-2磅/周体重减轻的强化干预。这项研究将探索和对比实验组和注意力控制组从登记到手术时间的身体质量指数(BMI)的变化，并监测能量摄入和体力活动的变化。这些变化将与下列终点有关：a)与癌症进展、激素状态、炎症和其他能量相关因素有关的选定循环生物标志物和基因表达的变化；b)肿瘤增殖和凋亡率；c)肿瘤标志物，例如胰岛素受体、血管内皮生长因子、AKT、NFkB和与激素、炎症和能效因子(首席)途径汇聚相关的磷蛋白；以及d)与功能和健康相关的结果。由于肿瘤组织和血液将从干预前到干预后进行检查，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袭性状态发展到侵袭性状态的途径。虽然建议超重和肥胖的乳腺癌幸存者进行更长期的减肥，但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伴随着手术前的短期体重减轻，这项研究提供了概念证据，即减肥可能提供一种可接受的补充治疗选择，可以与积极监测相结合，以进行长期管理。因此，提出的这项研究不仅将增加我们对负能量平衡对肿瘤生物学影响的了解，还可能改变护理标准，为每年被诊断为DCIS的50,000名美国妇女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.