Novel dietary interventions for reducing obesity-associated breast cancer

项目总结 尽管有新的治疗方法，乳腺癌的发病率近年来保持稳定， 在美国，每年新增25万例确诊病例和4万例死亡病例。与此同时，美国女性的比例 超重或肥胖的人数继续上升，并接近70%。肥胖和代谢性疾病( 发生在消瘦和肥胖的妇女中)会增加乳腺癌的发病率，并使患者的预后恶化 所有年龄段的人。绝经前肥胖的妇女患三阴性(TN)乳腺癌的风险增加(缺乏 任何有针对性的因素)。绝经后肥胖女性雌激素受体(ER)阳性乳房增多 癌症，更容易对内分泌治疗产生抵抗力。虽然雌激素显然是一种重要的 作为这种关系的一部分，两个关键的观察结果表明，在 作用：1)肥胖伴随着雌激素非依赖性三阴性乳腺癌较差的预后； 2)抗雌激素治疗对肥胖女性ER+乳腺肿瘤的疗效较差。不管 肿瘤亚型和绝经状态、超重与乳腺癌预后不良有关 病人。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这一标准 饮食减肥策略和体重恢复是很常见的。间歇性能量限制(IER)是一种新的饮食 减肥战略，可能对代谢健康和乳腺癌风险有更有利的影响 肿瘤进展。本提案中的工作将采用临床前、临床和干预研究，以 研究肥胖相关肿瘤进展的新机制以及创新的价值和可行性 消除肥胖对乳腺癌不利影响的饮食干预。 我们融合了营养学、肥胖症和医学肿瘤学的专业知识，以：1)研究癌症- 相关成纤维细胞(CAF)和肿瘤微环境(TME)可能在肥胖相关中发挥作用 肿瘤进展；2)研究IER新的饮食减肥策略是否可以消除肥胖相关 肿瘤进展；以及3)进行轨道IIa期概念验证研究，检查IER- 基于减肥干预的乳腺癌患者达到有意义的临床里程碑 超重和肥胖，并在未来的随机疗效试验中完善干预措施。 如果这项建议的目标得以实现，我们将拥有： *增进我们对肥胖与乳腺癌关系的理解，有证据表明肥胖与乳腺癌之间存在新的作用 CAF和TME在肥胖相关肿瘤促进TN和ER+乳腺癌中的作用； *为乳腺癌幸存者的IER减肥试验奠定了基础，数据将有助于我们 使这些策略适应这一患者群体的独特特征和需求；以及 *确定了有利于转移的TME的新的循环生物标记物，这可能有助于识别最 易患转移性疾病的

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.