Molecular & Genetic Determinants of Outcome in Breast Cancer

分子

• 批准号: 7364209
• 负责人: ANGELA DEMICHELE
• 金额: $ 29.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364209
• 关键词: Address; Adjuvant; Adjuvant Chemotherapy; Allogenic; Anthracycline Antibiotics; Anthracyclines; Apoptosis; Autologous; Autologous Bone Marrow Transplantation; Axillary lymph node group; Behavior; Biology; Breast; Breast Cancer Cell; Cancer Patient; Cell Cycle Regulation; Cell membrane; Characteristics; Clinical; Clinical Trials; Colorectal Cancer; Conduct Clinical Trials; Coronary Artery Bypass; DNA; Data; Development; Diagnosis; Disease; Disease-Free Survival; Distant; Eastern Cooperative Oncology Group; Enrollment; Environment; Epidermal Growth Factor Receptor; Estrogen Receptor Status; Estrogens; Exposure to; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Genotype; Germ Lines; High Dose Chemotherapy; IL6 gene; Immune response; In Situ Nick-End Labeling; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Institution; Integration Host Factors; Interleukin-6; Ki-67 Antigen; Knowledge; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Menopausal Status; Metastatic to; Microscopic; Modality; Molecular; Molecular Genetics; Multicenter Trials; Outcome; Parents; Pathologic; Pathway interactions; Patients; Peripheral; Phase III Clinical Trials; Physiological; Play; Positive Lymph Node; Postoperative Complications; Premenopause; Primary Neoplasm; Production; Prognostic Marker; Promoter Regions; Proto-Oncogene Proteins c-akt; Public Health; Randomized Controlled Clinical Trials; Rate; Recurrence; Reporting; Research Personnel; Residual state; Resistance; Risk; Risk Factors; Role; Serum; Severities; Signal Pathway; Signal Transduction; Site; Specimen; Staging; Staining method; Stains; Standards of Weights and Measures; Stem cell transplant; Stem cells; Techniques; Tissues; Toxic effect; Transplantation; Treatment Efficacy; Treatment Failure; Treatment outcome; Tumor Markers; Tumor Stem Cells; United States; Variant; Woman; base; cancer recurrence; cancer surgery; cohort; cyclooxygenase 2; cytokine; enzyme activity; follow-up; graft vs host disease; hazard; improved; interest; malignant breast neoplasm; neoplastic cell; outcome forecast; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; prognostic; programs; promoter; receptor; stem; trial comparing; tumor

DESCRIPTION (provided by applicant): Breast cancer remains a major public health problem, with over 190,000 new cases in the U.S. annually. Approximately 1/3 of these cases comprise women with disease limited to the breast and axillary lymph nodes. In these patients, aggressive multi-modality treatment can be curative in just over 50% of cases. However, current prognostic markers are unable to discriminate between those who will be cured with therapy, those who are cured without aggressive therapy and those who are destined to recur regardless of therapy. In order to improve survival and appropriately target therapies, better markers and improved understanding of the biology of recurrence is clearly needed. The proposed study seeks to expand our knowledge of breast cancer recurrence and prognosis by examining the role of host genetic characteristics on treatment outcome, and examining links between these host factors and tumor molecular characteristics. The host genetic factor of interest in this study is Interleukin-6 (IL-6), a pleiotropic cytokine involved in the host immune response to cancer. High serum levels of IL-6 are characteristic in breast cancer patients, and increased level is associated with aggressive disease, including more metastatic sites and resistance to standard therapies. Genetic polymorphisms in the promoter region of the IL-6 gene confer functional significance in transcription rates of the cytokine. We propose to examine the impact of these polymorphisms, individually and in combination, on disease-free survival (DFS) and overall survival (OS) in node-positive breast cancer patients. We propose to study this issue in the context of a large, multi-institution clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG). This study, a randomized trial comparing standard anthracycline-based adjuvant chemotherapy to high dose chemotherapy with autologous stem cell rescue in 540 women with at least 10 positive lymph nodes, will provide germ-line DNA (from stored stem cells), tumor specimens and substantial follow-up (5.7 years) to address four main hypotheses: (1) that IL-6 promoter polymorphisms are associated with DFS and OS in patients with node-positive breast cancer, (2) that this relationship is modified by estrogen receptor status of the tumor and menopausal status of the patient (3) that these polymorphisms are associated with specific alterations in tumor receptors and/or signaling that mediate the clinical outcomes and (4) that these polymorphisms are related to the toxicity of the treatments administered. We will utilize PCR-based genotyping techniques to identify the following polymorphism in the IL-6 promoter: -174G/C, -597G/A, -572G/C and -373AnTn. We will utilize immunohistochemical staining to identify alterations in tumor receptors (IL-6R, gp130, Her2/neu, EGFR), apoptosis (via TUNEL, STAT-1, STAT-3, bcl-2), cell cycle control (via MIB-1, AKT, p27) and cyclooxygenase-2 enzyme activity (COX-2), all of which have been shown to interact with IL-6 in vitro. Kaplan-Meier and Cox proportional hazards techniques will be used to investigate the associations of interest. This study will provide important information on interactions between genetic determinants of the host environment and tumor behavior, and will provide much-needed mechanistic data that will be important in utilizing this information for the development of targeted therapies for this devastating disease.

描述（由申请人提供）：乳腺癌仍然是一个主要的公共卫生问题，在美国每年有超过190,000个新病例。这些病例中约有三分之一是局限于乳房和腋窝淋巴结的妇女。在这些患者中，积极的多模式治疗可以治愈50%以上的病例。然而，目前的预后指标无法区分哪些人可以通过治疗治愈，哪些人不需要积极治疗就能治愈，哪些人无论治疗如何都注定会复发。为了提高生存率和适当的靶向治疗，显然需要更好的标志物和对复发生物学的更好理解。本研究旨在通过研究宿主遗传特征对治疗结果的作用，以及这些宿主因素与肿瘤分子特征之间的联系，扩大我们对乳腺癌复发和预后的认识。本研究中感兴趣的宿主遗传因子是白细胞介素-6 (IL-6)，这是一种参与宿主对癌症免疫反应的多效细胞因子。血清中IL-6水平高是乳腺癌患者的特征，升高的水平与侵袭性疾病有关，包括更多的转移部位和对标准治疗的耐药性。IL-6基因启动子区域的遗传多态性对细胞因子的转录率具有重要的功能意义。我们建议研究这些多态性（单独或联合）对淋巴结阳性乳腺癌患者的无病生存期（DFS）和总生存期（OS）的影响。我们建议在东部肿瘤合作小组（ECOG）进行的大型多机构临床试验的背景下研究这个问题。该研究是一项随机试验，比较标准蒽环类药物辅助化疗与自体干细胞拯救的高剂量化疗，540名至少有10个淋巴结阳性的妇女，将提供生殖系DNA（来自储存的干细胞），肿瘤标本和大量随访（5.7年），以解决四个主要假设：(1) IL-6启动子多态性与淋巴结阳性乳腺癌患者的DFS和OS相关；(2)这种关系受到肿瘤雌激素受体状态和患者绝经状态的影响；(3)这些多态性与肿瘤受体和/或介导临床结果的信号的特定改变有关；(4)这些多态性与所给治疗的毒性有关。我们将利用基于pcr的基因分型技术鉴定IL-6启动子中的以下多态性：-174G/C， -597G/A， -572G/C和-373AnTn。我们将利用免疫组织化学染色来鉴定肿瘤受体（IL-6R、gp130、Her2/neu、EGFR）、细胞凋亡（通过TUNEL、STAT-1、STAT-3、bcl-2）、细胞周期控制（通过mb -1、AKT、p27）和环氧化酶-2酶活性（COX-2）的变化，所有这些都已被证明在体外与IL-6相互作用。Kaplan-Meier和Cox比例风险技术将用于调查相关的利益。这项研究将为宿主环境的遗传决定因素与肿瘤行为之间的相互作用提供重要信息，并将提供急需的机制数据，这对于利用这些信息开发针对这种毁灭性疾病的靶向治疗非常重要。