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

身体成分和乳腺癌生存：乳腺肿瘤中的免疫和代谢生物标志物

• 批准号: 10665682
• 负责人: Elizabeth Marjorie Cespedes Feliciano
• 金额: $ 62.91万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665682
• 关键词: Address; Adipose tissue; Affect; Animal Model; Archives; Back; Biologic Characteristic; Biological Markers; Biology; Body Composition; Body Size; Breast Cancer Patient; Breast Cancer therapy; CD8-Positive T-Lymphocytes; Cancer Patient; Categories; Cell Proliferation; Cessation of life; Characteristics; Chronic; Classification; Clinical; Computerized Medical Record; Data; Diagnosis; Disease; Drug or chemical Tissue Distribution; ERBB2 gene; Ensure; Epidermal Growth Factor Receptor; Etiology; FRAP1 gene; Fatty acid glycerol esters; Future; Gene Expression; Hormonal; Hormone Receptor; Human; Immune; Immunity; Impairment; In Vitro; Inflammation; Intervention; Knowledge; Life Style; Link; Longterm Follow-up; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mediation; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Metabolism; Molecular; Molecular Epidemiology; Muscle; Obesity; Outcome; PIK3CG gene; Pathway interactions; Patient risk; Patients; Phenotype; Prognosis; Prognostic Factor; Proliferating; Proto-Oncogene Proteins c-akt; Recording of previous events; Recurrence; Recurrent Malignant Neoplasm; Research; Risk; Sample Size; Sampling; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic Intervention; Tumor Biology; Tumor Escape; Tumor Immunity; Tumor Markers; Tumor Subtype; Tumor Tissue; Up-Regulation; Visceral; Weight; Woman; anti-tumor immune response; breast cancer progression; breast cancer survival; cancer care; cancer recurrence; cancer risk; cancer subtypes; cancer therapy; cohort; data resource; epidemiology study; exhaust; exhaustion; experience; follow-up; hormone receptor-positive; immune function; improved; individualized medicine; interest; lifestyle intervention; malignant breast neoplasm; molecular subtypes; mortality; mortality risk; multidisciplinary; muscle form; nano-string; pharmacologic; pre-clinical; programmed cell death ligand 1; reduced muscle mass; sample archive; subcutaneous; treatment and outcome; treatment response; tumor; tumor microenvironment

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.

摘要 越来越多的证据表明，乳腺癌患者的不良身体成分（低肌肉质量和 过度肥胖）具有较差的治疗反应和增加的复发和死亡风险。低频 肌肉质量和过度肥胖会促进全身代谢异常，如代谢综合征。 虽然不良身体成分对局部肿瘤微环境的影响仍不清楚，但来自 临床前动物模型和体外分析表明，不良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传导途径的改变。但这些 尚未在人类乳腺癌患者或分子内全面研究这种关系。 乳腺癌的亚型具有不同的生物学和预后。发育和个性化乳房 癌症治疗将需要了解全身因素，如患者的身体成分和 代谢综合征影响局部乳腺肿瘤微环境，从而影响乳腺癌生存率。到 为了解决这一知识空白，我们提出了一项分子流行病学研究，以确定是否低肌肉 体重、过度肥胖和代谢综合征通过促进T- 细胞耗竭（Aim 1）和/或通过改变PI 3 K/AKT/mTOR途径和增殖信号传导的活性 (Aim 2）乳腺肿瘤微环境。我们将进一步确定这些免疫系统的改变， 代谢和增殖信号通路介导不良身体组成与 乳腺癌复发率和乳腺癌特异性死亡率（目标3）。为了实现这一目标，我们将 从一个独特的队列中选择的1，400个存档的临床乳腺肿瘤样本的基因表达水平：更多 对4,000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。所有这些患者都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个主要临床病理学类别中的每一个 因子受体2的状态，我们将能够检查协会的整体，并分别在每个乳房 癌症亚型利用这个首要的数据资源，我们将研究乳腺肿瘤的差异， 不良的身体组成和代谢综合征引起的微环境可能介导差异 乳腺癌的长期预后。这项研究将有助于个性化现有的乳腺癌 治疗和开发未来的干预方法，考虑肿瘤的分子特征， 和患者的身体组成。此外，这项研究将确定肿瘤生物标志物， 目标是在未来的试验中测量，以改善身体组成和代谢综合征， 药物或生活方式干预。