Determinants of Breast Cancer Survival

乳腺癌生存的决定因素

• 批准号: 6759467
• 负责人: MELISSA L. BONDY
• 金额: $ 63.86万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6759467
• 关键词: breast neoplasms; cancer information system; cancer risk; clinical research; family genetics; gene environment interaction; genetic markers; genetic polymorphism; histopathology; human genetic material tag; human subject; lifestyle; longitudinal human study; metastasis; multidrug resistance; neoplasm /cancer classification /staging; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplasm /cancer therapy; polymerase chain reaction; prognosis; racial /ethnic difference; restriction fragment length polymorphism; smoking; statistics /biometry

We propose a molecular epidemiologic cohort study of all newly diagnosed Stage IIA and IIB breast cancer patients who registered at The University of Texas M.D. Anderson Cancer Center (MDACC) between January 1, 1985 and December 31, 1999, and were residents of the state of Texas (N=2,875). This cohort is characterized by extensive long-term follow-up, and equal access to "best of care" practices. It offers us the opportunity to test hypotheses regarding the role of host genetic (i.e., such as gene polymorphisms in drug and radiation sensitivity, family history and ethnicity) and exposure factors (i.e., smoking, reproductive events, BMI, HRT, co-morbid conditions) in relation to tumor phenotype, as independent and interactive determinants of risk of recurrence, distant metastasis, contralateral breast cancer, second malignancies, and/or disease-free survival. In this population, we will examine a series of promising candidate host genetic markers and suspected environmental and lifestyle factors for their added value in clinical decision making when compared or combined with standard histopathological prognostic markers (e.g., lymph node status, tumor size, histological grade). In order to address our study hypotheses, we propose the following 4 specific aims: 1) To compile a comprehensive database of epidemiologic risk factors and clinical data (including treatment, pathology, and long-term follow-up) on all breast cancer patients seen exclusively at MDACC for Stage II disease. 2) To evaluate baseline epidemiologic profiles as independent and inter-related determinants of risk of recurrence, distant metastasis, contralateral breast cancer, new primary malignancies, and disease-free survival. These profiles will include comprehensive information on the use of tobacco, reproductive factors including ovarectomy and the use of HRT, body mass index (BMI), family history of cancer, age and ethnicity in relation to standard histopathology markers. 3) We will evaluate the interaction between these epidemiological factors and a) host and b) tumor molecular markers that show a relationship with disease prognosis and patient events. Specifically, in our sample set we will evaluate: the tumor specific expression of HER2-neu, Ki-67, ER, PR and p53, using standardized immunohistochemical analysis, as informative markers of tumor phenotype and patient performance. Inherited variability in genes that modulate host sensitivity to therapeutic agents, including the glutathione sulfotransferase (GSTpi, GSTM1, GSTT1); enzymes important in defending against chemical injury by catalyzing conjugation of reactive electrophilic molecules with glutathione, and an allele variant in the multi-drug resistance gene MDR-1 whose products, P- glycoprotein, is strongly linked with chemotherapeutic resistance. Our fourth aim is to construct statistical models to determine which marker or combination of markers and host factors (genetic and lifestyle) are better predictors of patient performance than the commonly used histopathologic methods.

我们建议对 1985 年 1 月 1 日至 1999 年 12 月 31 日期间在德克萨斯大学 MD 安德森癌症中心 (MDACC) 登记的所有新诊断的 IIA 和 IIB 期乳腺癌患者进行一项分子流行病学队列研究，并且是该州的居民。德克萨斯州（N=2,875）。 该群体的特点是广泛的长期随访，以及平等获得“最佳护理”实践的机会。 它为我们提供了测试有关宿主遗传作用（即药物和辐射敏感性的基因多态性、家族史和种族）和暴露因素（即吸烟、生殖事件、BMI、HRT、共病）的假设的机会。条件）与肿瘤表型相关，作为复发、远处转移、对侧乳腺癌、第二恶性肿瘤和/或无病生存风险的独立和相互作用的决定因素。在这个人群中，我们将检查一系列有前途的候选宿主遗传标记以及可疑的环境和生活方式因素，与标准组织病理学预后标记（例如淋巴结状态、肿瘤大小、组织学分级）进行比较或结合时，它们在临床决策中的附加价值）。 为了解决我们的研究假设，我们提出以下 4 个具体目标： 1) 编制所有乳腺癌患者的流行病学危险因素和临床数据（包括治疗、病理学和长期随访）的综合数据库MDACC 专门针对 II 期疾病。 2) 评估基线流行病学特征作为复发、远处转移、对侧乳腺癌、新原发性恶性肿瘤和无病生存风险的独立和相互关联的决定因素。 这些概况将包括关于烟草使用、生殖因素（包括卵巢切除术和激素替代疗法的使用）、体重指数（BMI）、癌症家族史、与标准组织病理学标志物相关的年龄和种族的综合信息。 3) 我们将评估这些流行病学因素与 a) 宿主和 b) 肿瘤分子标志物之间的相互作用，这些标志物显示与疾病预后和患者事件的关系。具体来说，在我们的样本集中，我们将使用标准化免疫组织化学分析评估 HER2-neu、Ki-67、ER、PR 和 p53 的肿瘤特异性表达，作为肿瘤表型和患者表现的信息标记。 调节宿主对治疗药物敏感性的基因遗传变异，包括谷胱甘肽磺基转移酶（GSTpi、GSTM1、GSTT1）；通过催化反应性亲电分子与谷胱甘肽的结合，在防御化学损伤中发挥重要作用的酶，以及多药耐药基因 MDR-1 中的等位基因变体，其产物 P-糖蛋白与化疗耐药性密切相关。 我们的第四个目标是构建统计模型，以确定哪种标记或标记与宿主因素（遗传和生活方式）的组合比常用的组织病理学方法更能预测患者的表现。