Novel dietary interventions for reducing obesity-associated breast cancer

项目摘要 尽管有新的治疗方式，近年来乳腺癌的发病率保持稳定， 在美国，每年有超过25万例新诊断和超过4万例死亡。与此同时，美国女性的比例 超重或肥胖的比例继续上升，接近70%。肥胖和代谢性疾病（ 发生在瘦和肥胖女性）增加乳腺癌的发病率，并使 所有年龄段肥胖的绝经前妇女患三阴性（TN）乳腺癌的风险增加（缺乏 任何目标因素）。绝经后肥胖妇女雌激素受体（ER）阳性乳腺癌发生率 癌症，更有可能对内分泌疗法产生耐药性。虽然雌激素显然是一个重要的 作为这种关系的一部分，两个关键的观察结果表明， 发挥：1）肥胖伴随着雌激素非依赖性三阴性乳腺癌的预后较差; 2)抗雌激素疗法对肥胖妇女的ER+乳腺肿瘤的效果较差。无论 肿瘤亚型和绝经状态，超重与乳腺癌预后不良相关 患者众所周知，减肥可以改善乳腺癌的预后，但大多数人无法维持标准 饮食减肥策略和体重反弹是常见的。间歇性能量限制（IER）是一种新型的饮食 减肥策略，可能对代谢健康和乳腺癌风险产生更有益的影响， 肿瘤进展。本提案中的工作将采用临床前、临床和干预性研究， 研究肥胖相关肿瘤进展的新机制，以及创新治疗的价值和可行性。 饮食干预以消除肥胖对乳腺癌的不利影响。 我们将营养、肥胖和肿瘤医学方面的专业知识结合在一起，以：1）研究癌症的新作用- 相关的成纤维细胞（CAFs）和肿瘤微环境（TME）可能在肥胖相关的 肿瘤进展; 2）研究IER的新饮食减肥策略是否可以消除肥胖相关的 肿瘤进展;和3）进行ORBIT IIa期概念验证研究，检查IER- 基于减肥干预，以达到有意义的临床里程碑，乳腺癌患者患有 超重和肥胖，并在未来的随机疗效试验中改进干预措施。 如果这项建议的目标得以实现，我们将： * 我们进一步了解肥胖与乳腺癌的关系，有证据表明， CAF和TME在TN和ER+乳腺癌的肥胖相关肿瘤促进中的作用; * 为乳腺癌幸存者的IER减肥试验奠定了基础，数据将帮助我们 使这些策略适应该患者人群的独特特征和需求;以及 * 确定了促转移性TME的新型循环生物标志物，这可能有助于最大限度地识别患者 易患转移性疾病。

PROJECT SUMMARY Despite new treatment modalities, the incidence of breast cancer has remained steady in recent years with >250,000 new diagnoses and >40,000 deaths annually in the US. Concurrently, the proportion of US women with overweight or obesity continues to rise, and is approaching 70%. Obesity and metabolic disease (which occurs in lean and obese women) increase breast cancer incidence and worsen patient outcomes in women of all ages. Premenopausal women with obesity are at increased risk of triple negative (TN) breast cancer (lacking any targetable factors). Postmenopausal women with obesity incur more estrogen receptor (ER) positive breast cancer and are more likely to develop resistance to endocrine therapies. While estrogen is clearly an important part of this relationship, two key observations suggest that there may be estrogen-independent mechanisms at play: 1) obesity is accompanied by worse prognosis for estrogen-independent triple negative breast cancer; and 2) anti-estrogen therapies are less effective against ER+ breast tumors in women with obesity. Regardless of tumor subtype and menopausal status, excess weight is associated with poor outcomes for breast cancer patients. Weight loss is known to improve breast cancer outcomes, but most people cannot sustain the standard dietary weight loss strategies and weight regain is common. Intermittent energy restriction (IER) is a novel dietary weight loss strategy that may have more beneficial effects on metabolic health and on breast cancer risk and tumor progression. The work in this proposal will employ preclinical, clinical, and interventional studies, to examine a novel mechanism of obesity-associated tumor progression and the value and feasibility of innovative dietary interventions for eliminating obesity’s adverse effects on breast cancer. We have merged expertise in nutrition, obesity, and medical oncology to: 1) examine a novel role that cancer- associated fibroblasts (CAFs) and the tumor microenvironment (TME) may be playing in obesity-associated tumor progression; 2) investigate if the novel dietary weight loss strategy of IER can eliminate obesity-associated tumor progression; and 3) perform an ORBIT Phase IIa proof-of-concept study examining the ability of an IER- based weight loss intervention to reach meaningful clinical milestones in breast cancer patients afflicted with overweight and obesity and refine the intervention for delivery in a future randomized efficacy trial. If the objectives of this proposal are achieved, we will have: * Advanced our understanding of the obesity – breast cancer relationship, with evidence of a novel role for CAFs and the TME in obesity-associated tumor promotion for TN and ER+ breast cancer; * Established the foundation for IER weight loss trials in breast cancer survivors, with data that will help us adapt these strategies to the unique characteristics and needs of this patient population; and * Identified novel circulating biomarkers of a pro-metastatic TME, which may help identify patients most susceptible to metastatic disease.