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是正常体重女性的两倍。大量的临床前研究表明，热量限制对动物的癌症进展有好处——但是，在人类身上会看到类似的效果吗？为了响应对转化研究的呼吁，以确定减肥可能影响癌症预后的生物学/生物行为途径（PAR-12-229），我们提出了一项试点研究，该研究建立在我们成功的术前干预的基础上，以回答研究问题，“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作用？”我们将随机分配40名超重或肥胖的绝经后诊断为导管原位癌（DCIS）（浸润性癌症的前兆）并选择乳房切除术或乳房肿瘤切除术的妇女到1 / 2研究组：1)一个注意力控制组，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进行性阻力训练（PRT）；或2实验组，接受PRT和指导，纠正营养不足，加上强化干预，通过饮食、运动和行为改变促进每周体重减轻1.5-2磅。本研究将探索和对比实验组和注意力控制组从入组到手术时的身体质量指数（BMI）变化，并监测能量摄入和身体活动的变化。这些变化将与以下终点相关：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)肿瘤增殖和凋亡率；c)肿瘤标志物，如胰岛素受体、VEGF、AKT、NFkB和与激素、炎症和能量评级因子（CHIEF）通路相关的磷酸化蛋白；d)功能和健康相关的结果。因为从干预前到干预后，肿瘤组织和血液都将被检查，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入性到侵入性进展的途径。虽然建议超重和肥胖的乳腺癌幸存者长期减肥，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手术前的短期体重减轻中，本研究提供了一个概念的证据，即体重减轻可能是一种可接受的补充治疗选择，可以与主动监测相结合，进行长期管理。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.