Body composition and breast cancer survival: immune and metabolic biomarkers in breast tumors

摘要 越来越多的证据表明，身体成分不良的乳腺癌患者(低肌肉质量和 过度肥胖)的治疗反应较差，复发和死亡的风险增加。都很低 肌肉质量和过度肥胖会促进全身代谢异常，如代谢综合征。 虽然身体不良成分对局部肿瘤微环境的影响尚不清楚，但来自 临床前动物模型和体外分析表明，不利的身体成分可能有助于 抗肿瘤免疫受损以及代谢和增殖信号通路的改变。然而，这些 人类乳腺癌患者之间的关系尚未得到全面研究，也没有在分子水平上进行研究。 生物学和预后不同的乳腺癌亚型。乳房的发展和个性化 癌症治疗将需要了解系统性因素，如患者的身体成分和 代谢综合征会影响局部乳腺肿瘤的微环境，从而影响乳腺癌的生存。至 为了解决这一认识上的差距，我们提出了一项分子流行病学研究，以确定下肌肉是否 体重、过度肥胖和代谢综合征通过促进T细胞分泌而损害抗肿瘤免疫反应。 细胞耗竭(目标1)和/或通过改变PI3K/AKT/mTOR通路和增殖信号的活性 (目的2)在乳腺肿瘤微环境中。我们将进一步确定这些变化是否具有免疫力， 代谢和增殖信号通路介导不良身体成分与 乳腺癌复发和乳腺癌特有死亡率(目标3)。为了实现这一目标，我们将采取措施 从一个独特的队列中挑选的1400个存档的临床乳腺癌样本中的基因表达水平：更多 对4000多名II期和III期乳腺癌患者进行纵向随访和精确的肌肉测量， 皮下和内脏脂肪组织。这些患者还拥有丰富的电子病历数据 癌症治疗和代谢综合征。由于我们的抽样方法确保了 由激素受体和人类表皮生长定义的四种主要临床病理类型 因子受体2状态，我们将能够全面和单独地检查每个乳房内的关联 癌症亚型。使用这个主要的数据资源，我们将检查乳腺肿瘤的差异 不良身体成分和代谢综合征引起的微环境可能调节差异 对乳腺癌的长期预后有影响。这项拟议的研究将有助于使现有的乳腺癌个体化。 治疗和开发未来的干预方法，既考虑肿瘤的分子特征 和病人的身体成分。此外，这项研究将确定合适的肿瘤生物标记物。 在未来的试验中测量的目标，以改善身体成分和代谢综合征，通过 药理学或生活方式干预。

ABSTRACT There is growing evidence that breast cancer patients with adverse body composition (low muscle mass and excess adiposity) have worse therapeutic responses and an increased risk of recurrence and death. Both low muscle mass and excess adiposity promote systemic metabolic abnormalities like the metabolic syndrome. While the impact of adverse body composition on the local tumor microenvironment remains unclear, data from pre-clinical animal models and in vitro analyses suggest that adverse body composition could contribute to impaired anti-tumor immunity and alterations in metabolic and proliferative signaling pathways. However, these relationships have not been comprehensively studied in human breast cancer patients or within molecular subtypes of breast cancer that have differing biology and prognosis. Developing and personalizing breast cancer therapies will require understanding how systemic factors such as patient body composition and the metabolic syndrome impact the local breast tumor microenvironment and therefore breast cancer survival. To address this gap in knowledge, we propose a molecular epidemiologic study to determine if lower muscle mass, excess adiposity and the metabolic syndrome impair the anti-tumor immune response by promoting T- cell exhaustion (Aim 1) and/or by altering the activity of PI3K/AKT/mTOR pathways and proliferative signaling (Aim 2) in the breast tumor microenvironment. We will further determine if alterations in these immune, metabolic and proliferative signaling pathways mediate the association of adverse body composition with breast cancer recurrence and breast cancer-specific mortality (Aim 3). To accomplish this, we will measure gene expression levels in 1,400 archived clinical breast tumor samples selected from a unique cohort: more than 4,000 stage II and III breast cancer patients with longitudinal follow-up and precise measures of muscle, subcutaneous, and visceral adipose tissue. All these patients also have rich electronic medical record data on cancer treatments and the metabolic syndrome. Since our sampling approach ensures representation across each of four major clinicopathological categories defined by hormone receptor and human epidermal growth factor receptor 2 status, we will be able to examine associations overall, and separately within each breast cancer subtype. Using this premier data resource, we will examine how differences in the breast tumor microenvironment caused by adverse body composition and the metabolic syndrome may mediate differences in long-term breast cancer outcomes. The proposed study will help personalize existing breast cancer therapies and develop future intervention approaches that consider both the molecular features of the tumor and patient body composition. Furthermore, this study will identify tumor biomarkers that are appropriate targets to be measured in future trials to improve body composition and the metabolic syndrome through pharmacologic or lifestyle intervention.