Molecular Profiles and Lifestyle Factors in Breast Cancer Prognosis

描述(申请人提供)：近年来，新技术使我们能够更好地描述乳腺癌的异质性，并根据它们的分子图谱识别一些生物学亚型。因此，肿瘤的分子分类越来越多地被用于指导治疗选择和新的治疗方法的开发，在评估预后和病因学研究中。一种分子分类--“固有亚型”--根据起源的细胞类型(管腔A/B或基底细胞)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。这项建议的主要目标是在北加州凯撒永久医疗计划(KPNC)内对乳腺癌幸存者(N=4177)进行的两项正在进行的队列研究中，检查固有亚型的影响及其与乳腺癌风险因素和短期和长期预后的关系。第一项研究，癌症后生活流行病学(LACE)队列，是一个基于人群的队列，包括2288名被诊断为I&GT；1 cm、II或IIIa期乳腺癌的女性，成立于2000-2002年，目的是检查行为因素和乳腺癌预后。这些数据将与路径队列中另外1890例类似阶段的病例结合起来，这是一项始于2006年1月的针对短期乳腺癌幸存者的研究。鉴于到目前为止，能量相关因素与预后之间的研究结果不一致，以及暗示影响可能因肿瘤特征而异，如激素受体状态，这项建议的第二个目标是检查与能量平衡相关的特定行为是否可能与乳腺癌患者的预后有关，或者主要与某些固有亚型的女性相关，因为大多数研究只报道了能量相关因素对短期预后的影响，该建议的另一个次要目标是继续跟踪蕾丝队列中的女性，直到诊断后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关于体重、体重变化、体力活动和饮食的数据。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，并使用免疫组织化学分析(IHC)将乳腺癌分类为固有亚型。这项研究将通过检查两个现有癌症幸存者队列中提出的问题来实现巨大的成本节约，这些队列中的癌症幸存者的行为后诊断数据已经可用，并通过检索队列中的肿瘤样本，其中近90%的女性属于KPNC，这是一个HMO，在那里可以很容易地获得肿瘤样本。我们的建议解决了一系列问题，这些问题是癌症生存研究中新出现的优先领域，将对临床和公共卫生产生影响。公共卫生相关性：少数样本相对较少或短期随访的研究已将肿瘤分类为固有亚型，并研究了它们与临床肿瘤特征或生存的关系。更少的人关注过乳腺癌的风险因素。这项研究建议的Lace和Path联合队列是针对乳腺癌幸存者的最大资源之一，这些患者已经从医疗表收集了临床数据，从自我管理的问卷中收集了生活方式和其他因素。建议的固有亚型(IHC)分子标记的加入为乳腺癌亚型分类提供了一种创新且经济高效的方法(可以对存档的肿瘤组织进行IHC分析)，这将提高我们对预后变化的理解，并允许分子和行为信息的独特组合，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，这些信息具有临床和公共卫生意义。这个以人群为基础的队列在解决我们关于癌症存活率的知识中的几个重要缺口方面具有独特的地位。

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.