Prospective Study of Breast Cancer Survivorship

描述（由申请人提供）：尽管乳腺癌妇女的生活方式发生了重大变化，如饮食或使用补充和替代药物（CAM），但很少有研究探讨这些因素是否能改善预后。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部分取决于分子特征，如影响氧化损伤或DNA修复的遗传多态性，或影响基因表达的异常DNA甲基化。这些标志物本身可能影响预后或与常规治疗相互作用。我们建议通过建立迄今为止最大的乳腺癌女性前瞻性队列研究来解决这些知识差距。 我们将从北方加州的Kaiser Permanente（KPNC）招募至少5,021名乳腺癌女性。通过计算机病理报告，我们可以非常快速地确定病例，因为它们是组织学证实的乳腺癌病例，最大限度地减少生存偏差。我们将采访并向参与者发送问卷，并从医疗图表和KPNC数据库中提取数据。将在治疗前采集血液样本以表征遗传多态性，并将获得肿瘤标本以检查异常DNA甲基化。血液样本和乳腺肿瘤DNA也将储存起来供将来使用。 这一资源将使研究复发和生存的影响：1）生活方式因素，包括饮食，体力活动，CAM的使用和生活质量; 2）宿主和肿瘤分子特征，包括遗传多态性（例如，参与：环磷酰胺（CYP 3A 4、GSTP 1、GSTA 1）或他莫昔芬代谢（SULTIA 1）;抗氧化损伤保护（MnSOD、CAT、GPX 1、GSTM 1、GSTT 1）;和DNA修复（XRCC 1、LIG 4、XRCC 3、XPD、ERCC 1、APE 1）），以及乳腺肿瘤中基因的异常DNA甲基化（BRCA 1、P161 NK 4a、E-钙粘蛋白、磷脂酰肌醇蛋白聚糖3、DUTT 1、DUTM 1、TSLC 1、DAP-激酶、GSTP 1）。 使用比例风险回归，我们将研究生活方式因素和分子标志物对复发和死亡风险的相关性;我们估计在5年的资助期内至少有599例复发和331例死亡。对于生存率，我们将有能力检测到1.64的相对风险，比较连续暴露（如营养摄入）的上四分位数和下四分位数，以及患病率为0.10的暴露的相对风险为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.