Molecular Profiles and Lifestyle Factors in Breast Cancer Prognosis

描述（由申请人提供）：近年来，新技术使我们能够更好地表征乳腺癌的异质性，并根据其分子谱识别出许多生物学亚型。因此，肿瘤的分子分类越来越多地用于指导治疗选择和新治疗方案的开发、预后评估和病因研究。一种分子分类，即“内在亚型”，根据其起源细胞类型（腔内A/B或基底）或肿瘤是否her2阳性来区分乳腺癌，已被用于识别生物学和临床上不同的乳腺癌亚型。本提案的主要目的是在两项正在进行的乳腺癌幸存者队列研究（N=4177）中，研究内在亚型的影响及其与乳腺癌危险因素和短期和长期预后的关系，这些研究是在北加州凯撒医疗保健（KPNC）项目中进行的。第一项研究，癌症后的生活流行病学（LACE）队列，是一个基于人群的队列研究，在2000- 2002年建立，研究2288名诊断为I期bbb10、II或IIIa期乳腺癌的妇女，以检查行为因素和乳腺癌预后。这些数据将与来自Pathways队列的1890例其他类似阶段的病例相结合，Pathways队列是一项于2006年1月开始的短期乳腺癌幸存者研究。鉴于迄今为止在能量相关因素与预后之间观察到的结果不一致，并且表明影响可能因肿瘤特征（如激素受体状态）而异，本研究的第二个目标是研究与能量平衡相关的特定行为是否与乳腺癌患者的总体预后有关，或者主要与具有某些内在亚型的女性预后有关。该建议的另一个次要目标是继续跟踪LACE队列中的女性直至诊断后15年，并检查与能量相关的生活方式因素与长期预后的关系。在诊断后的多个时间点收集体重、体重变化、体力活动和饮食数据。每年通过自我报告跟踪妇女的复发和死亡情况，并通过医疗记录和死亡证明进行核实。在拟议的新资助期内，将检索存档的肿瘤块，并使用免疫组化分析（IHC）将乳腺癌分类为内在亚型。本研究将通过在两个现有的癌症幸存者队列中检查所提出的问题（他们的诊断后行为数据已经可用）和在一个接近90%的妇女属于KPNC（一个HMO）的队列中检索肿瘤标本（肿瘤标本很容易获得）来实现巨大的成本节约。我们的提案解决了一系列癌症生存研究中正在出现的优先领域的问题，这些问题将对临床和公共卫生产生影响。公共卫生相关性：数量有限的样本相对较小或短期随访的研究将肿瘤分类为内在亚型，并检查其与临床肿瘤特征或生存的关系。更少的人研究了乳腺癌的风险因素。本研究提出的联合LACE和Pathways队列构成了乳腺癌幸存者的最大资源之一，已经收集了来自医疗图表、生活方式和自我管理问卷的其他因素的临床数据。提出的内在亚型（IHC）分子标记的加入为乳腺癌亚型分类提供了一种创新和经济有效的方法（IHC检测可以在存档的肿瘤组织上进行），这将提高我们对预后变化的理解，也允许分子和行为信息的独特结合，以帮助更好地了解哪些女性最有可能从乳腺癌诊断后生活方式的改变中受益。具有临床和公共卫生意义的信息。这个以人群为基础的队列具有独特的定位，可以解决我们关于癌症生存知识中的几个重要空白。

DESCRIPTION (provided by applicant): In recent years, new technologies have allowed us to better characterize the heterogeneity of breast cancer and to identify a number of biological subtypes based on their molecular profiles. Consequently, molecular classification of tumors is increasingly being used to guide treatment selection and new treatment development, in evaluating prognosis, and in studies of etiology. One molecular classification, the "intrinsic subtype", which distinguishes among breast cancers based on either their cell type of origin (luminal A/B or basal) or whether the tumor is HER2-positive, has been used to identify biologically and clinically distinct subtypes of breast cancer. The primary goal of this proposal is to examine the effects of intrinsic subtypes and their relationship to breast cancer risk factors and short and long-term prognosis in two ongoing cohort studies of breast cancer survivors (N=4177) being conducted within the Kaiser Permanente of Northern California (KPNC) Medical Care program. The first study, the Life After Cancer Epidemiology (LACE) cohort, a population-based cohort of 2,288 women diagnosed with Stage I>1 cm, II, or IIIa breast cancer, was established in 2000- 2002 to examine behavioral factors and breast cancer prognosis. These data will be combined with 1890 additional cases of similar stage from the Pathways cohort, a study of short term breast cancer survivors which began in January 2006. Given the inconsistency observed to date in findings between energy related factors and prognosis and the suggestion that effects may vary by tumor characteristics such as hormone receptor status, a secondary goal of this proposal is to examine whether specific behaviors related to energy balance may be related to prognosis among breast cancer patients in general or primarily among women with certain intrinsic subtypes Since most studies have only reported on effects of energy related factors on short term prognosis, another secondary goal of this proposal is to continue to follow women in the LACE cohort up until 15 year post-diagnosis and to examine the relationship of energy related lifestyle factors with long-term prognosis. Data on weight, weight change, physical activity and diet were collected at multiple time points post diagnosis. Women are followed annually for recurrence and death by self report and verified by medical record and death certificates. During the proposed new funding period, archived tumor blocks will be retrieved and, using immunohistochemical assays (IHC), breast cancers will be classified into intrinsic subtypes. This study will achieve tremendous cost savings by examining the proposed questions within two existing cohort of cancer survivors for whom post diagnosis data on behavior are already available and by retrieving tumor specimens within a cohort where close to 90% the women belong to the KPNC, an HMO, where tumor specimens are readily accessible. Our proposal addresses a range of issues that are emerging priority areas in cancer survivorship research which will have both clinical and public health impact. PUBLIC HEALTH RELEVANCE: A limited number of studies with relatively small samples or short-term follow-up have classified tumors into intrinsic subtypes and examined their association with clinical tumor characteristics or survival. An even smaller number have looked at breast cancer risk factors. The combined LACE and Pathways cohorts, as proposed in this study constitutes one of the largest resources on breast cancer survivors with already collected clinical data from medical charts and lifestyle and other factors from self- administered questionnaires. The addition of the proposed intrinsic subtype (IHC) molecular markers to this resource provides an innovative and cost-efficient method for classifying breast cancer subtypes (IHC assays can be done on archived tumor tissue) that will improve our understanding of variation in prognosis, and also allows for the unique combination of molecular and behavioral information to help better understand which women are most likely to benefit from changes in lifestyle after a breast cancer diagnosis, information of both clinical and public health significance. This population-based cohort is uniquely positioned to address several important gaps in our knowledge about cancer survivorship.