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

基本信息

批准号：
10029647
负责人：
Elizabeth Marjorie Cespedes Feliciano
金额：
$ 69.91万
依托单位：
KAISER FOUNDATION RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/10029647
关键词：
1-Phosphatidylinositol 3-Kinase 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 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 Impairment In Vitro Inflammation Intervention Knowledge Lead Life Style Link Longterm Follow-up Malignant Neoplasms Mammary Neoplasms Measures Mediating Mediation Metabolic Metabolic Pathway Metabolic dysfunction Metabolic syndrome Metabolism Molecular Muscle Obesity Outcome Pathway interactions Patient risk Patients Pharmacology Phenotype Prognostic Factor Proto-Oncogene Proteins c-akt Recording of previous events Recurrence Research Risk Sample Size Sampling Signal Pathway Signal Transduction T-Lymphocyte Testing Therapeutic Intervention Treatment outcome Tumor Biology Tumor Escape Tumor Immunity Tumor Markers Tumor Subtype Tumor Tissue Up-Regulation Visceral Weight Woman anti-tumor immune response base 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 outcome forecast pre-clinical programmed cell death ligand 1 reduced muscle mass subcutaneous treatment response tumor tumor microenvironment

项目摘要

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.

抽象的越来越多的证据表明乳腺癌患者患有不良身体成分（肌肉质量低和过度肥胖）的治疗反应较差，复发和死亡的风险增加。都低肌肉质量和过度肥胖会促进全身代谢异常，例如代谢综合征。尽管不良身体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，不良身体组成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。但是，这些在人类乳腺癌患者或分子中尚未全面研究关系具有不同生物学和预后的乳腺癌亚型。发展和个性化乳房癌症疗法将需要了解患者身体组成等系统因素如何代谢综合征影响局部乳腺肿瘤微环境，因此影响乳腺癌的存活。到在知识上解决这一差距，我们提出了一项分子流行病学研究，以确定较低的肌肉是否较低质量，过量肥胖和代谢综合征通过促进T-来损害抗肿瘤免疫反应细胞耗尽（AIM 1）和/或通过改变PI3K/AKT/MTOR途径的活性和增殖信号传导（AIM 2）在乳腺肿瘤微环境中。我们将进一步确定这些免疫的改变是否代谢和增殖信号通路介导了不良身体组成与乳腺癌复发和乳腺癌特异性死亡率（AIM 3）。为此，我们将衡量从独特队列中选择的1,400个存档临床乳腺肿瘤样品中的基因表达水平：更多超过4,000阶段II和III乳腺癌患者，具有纵向随访和肌肉的精确度量皮下和内脏脂肪组织。所有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可确保遍历由激素受体和人表皮生长定义的四个主要临床病理类别中的每一个因子受体2状态，我们将能够整体检查关联，并在每个乳房内分别检查癌症亚型。使用此主要数据资源，我们将研究乳腺肿瘤的差异由不良身体组成和代谢综合征引起的微环境可能介导差异在长期的乳腺癌结果中。拟议的研究将有助于个性化现有的乳腺癌疗法并开发未来的干预方法，这些方法都考虑了肿瘤的分子特征和患者的身体成分。此外，这项研究将确定合适的肿瘤生物标志物将来的试验中要测量的靶标，以改善人体组成和通过药理或生活方式干预。