Prospective Study of Breast Cancer Survivorship

描述(申请人提供)：尽管乳腺癌患者的生活方式发生了很大的变化，如饮食或补充和替代药物(CAM)的使用，但很少有研究研究这些因素是否会改善预后。这些因素也可能影响生活质量，进而影响预后。这些因素如何影响预后可能在一定程度上取决于分子特征，如影响氧化损伤或DNA修复的基因多态，或影响基因表达的异常DNA甲基化。这些标记物本身可能会影响预后或与传统疗法相互作用。我们建议通过建立迄今最大规模的乳腺癌女性前瞻性队列研究来解决这些知识差距。 我们将从北加州凯撒永久医院(KPNC)招募至少5,021名患有乳腺癌的女性。通过计算机病理报告极快地确定病例，我们可以在组织学确认的情况下识别乳腺癌病例，最大限度地减少生存偏见。我们将采访参与者并向他们发送问卷，并从医疗图表和KPNC数据库中提取数据。治疗前将采集血液样本以确定基因多态的特征，并将获得肿瘤样本以检查异常的DNA甲基化。血液样本和乳腺肿瘤DNA也将被储存起来，以备将来使用。 这一资源将有助于研究以下因素对复发和存活的影响：1)生活方式因素，包括饮食、体力活动、使用CAM和生活质量；2)宿主和肿瘤分子特征，包括遗传多态(例如，涉及环磷酰胺(CYP3A4、GSTP1、GSTA1)或他莫昔芬代谢(SULTIA1)的那些；抵御氧化损伤的保护(MnSOD、CAT、GPX1、GSTM1、GSTT1)；和DNA修复(XRCC1、LIG4、XRCC3、XPD、ERCC1、APE1)和乳腺肿瘤中基因的异常DNA甲基化(BRCA1、P161NK4a、E-钙粘附素、Glypican3、DUTT1、HIC1、TSLC1、DAP-Kinase、GSTP1)。 使用比例风险回归，我们将检查生活方式因素与复发和死亡风险的分子标志物之间的关系；我们估计在5年资助期内至少有599例复发和331例死亡。对于生存，我们将有能力检测到持续暴露的相对危险为1.64，对比营养摄入量等持续暴露的上四分之一和下四分之一，如果暴露的流行率为0.10，相对危险为159。这项研究将提供一些关于这些危险因素和乳腺癌预后的初步信息。

DESCRIPTION (provided by applicant): Despite substantial lifestyle changes such as in diet or use of complementary and alternative medicine (CAM) among women with breast cancer, few studies have examined whether such factors improve prognosis. These factors may also influence quality of life, which may in turn influence prognosis. How these factors influence prognosis may depend in part on molecular characteristics such as genetic polymorphisms that influence oxidative damage or DNA repair, or aberrant DNA methylation which influences gene expression. These markers may themselves influence prognosis or interact with conventional therapies. We propose to address these gaps in knowledge by establishing the largest prospective cohort study of women with breast cancer to date. We will enroll at least 5,021 women with breast cancer from Kaiser Permanente of Northern California (KPNC). With extremely rapid case ascertainment through computerized pathology reports, we can identify cases of breast cancer as they are confirmed histologically, minimizing survival bias. We will interview and send questionnaires to participants, and extract data from medical charts and KPNC databases. Blood samples will be collected prior to treatment to characterize genetic polymorphisms, and tumor specimens will be obtained to examine aberrant DNA methylation. Blood samples and breast tumor DNAs will also be banked for future use. This resource will enable study of the effects on recurrence and survival of: 1) lifestyle factors, including diet, physical activity, use of CAM, and quality of life; and, 2) host and tumor molecular characteristics, including genetic polymorphisms (e.g., those involved in: cyclophosphamide (CYP3A4, GSTP1, GSTA1) or tamoxifen metabolism (SULTIA1); protection against oxidative damage (MnSOD, CAT, GPX1, GSTM1, GSTT1); and DNA repair (XRCC1, LIG4, XRCC3, XPD, ERCC1, APE1)), and aberrant DNA methylation of genes in breast tumors (BRCA1, P161NK4a, E-Cadherin, glypican3, DUTT1, HIC1, TSLC1, DAP-kinase, GSTP1). Using proportional hazards regression, we will examine associations of lifestyle factors and molecular markers on risk of recurrence and mortality; we estimate at least 599 recurrences and 331 deaths during the 5-year funding period. For survival, we will have power to detect a relative hazard of 1.64 comparing upper to lower quartiles of continuous exposures such as nutrient intake, and a relative hazard of 159 for an exposure with prevalence of 0.10. This study will provide some of the first information on these risk factors and breast cancer prognosis.