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的身体成分不良（肌肉质量低和过度肥胖）的治疗反应较差，并且复发和死亡的风险增加。两者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。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会导致抗肿瘤免疫力受损以及代谢和增殖信号通路的改变。然而，这些尚未对人类乳腺癌患者或分子内的关系进行全面研究具有不同生物学和预后的乳腺癌亚型。乳房的发育和个性化癌症治疗需要了解全身因素（例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，从而影响乳腺癌的生存。到为了解决这一知识差距，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- 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 通路和增殖信号传导的活性（目标 2）乳腺肿瘤微环境。我们将进一步确定这些免疫是否发生改变，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异性死亡率（目标 3）。为了实现这一目标，我们将测量选自独特队列的 1,400 个存档的临床乳腺肿瘤样本中的基因表达水平：更多对超过 4,000 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跨领域的代表性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 状态，我们将能够检查整体关联以及每个乳房内的单独关联癌症亚型。使用这一主要数据资源，我们将研究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介导差异乳腺癌的长期结果。拟议的研究将有助于个性化现有的乳腺癌治疗并开发未来的干预方法，同时考虑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未来试验中要测量的目标，通过以下方式改善身体成分和代谢综合征药物或生活方式干预。