CONFIRMATION STUDIES OF BLOOD BASED BIOMARKERS OF RISK FOR BREAST CANCER

描述（由申请人提供）：存在识别乳腺癌风险生物标志物的实质性需求。一种深入的定量蛋白质组学方法被应用于分析在诊断乳腺癌之前收集的血浆，以寻找这种疾病的风险的候选标志物。这些样本来自妇女健康倡议（WHI）队列，包括在采血后7年内诊断为乳腺癌的妇女和年龄、自我报告的种族、子宫切除术状态和入组日期相匹配的对照组。在平行研究中，蛋白质组学分析应用于基线和结合马雌激素（CEE）或CEE/MPA（醋酸甲羟孕酮）激素治疗（HT）一年后获得的血液标本。广泛的蛋白质组学分析确定了受HRT影响的循环蛋白质的一个大的子集，并且还产生了一组值得进行额外验证研究的乳腺癌风险标志物候选物。有趣的是，一些风险候选人也受到HRT的影响，因此可能有助于阐明与CEE/MPA治疗相关的乳腺癌风险。在目标1中，我们建议使用来自WHI激素治疗试验的一组独立的WHI参与者进行风险标志物的确认研究，这些参与者患有乳腺癌并匹配对照。在14个待确认研究的候选样品中，有8个具有ELISA，可以进行检测。其余的候选物将使用多反应监测质谱法进行确认。第二个目的是评估已确定的风险标志物作为激素治疗对乳腺癌影响的介质。为此，将使用CEE和CEE/MPA试验中基线和HT 1年时收集的血浆来确定病例和匹配对照中候选风险标志物浓度的变化。拟议的项目有可能有助于临床相关的乳腺癌生物标志物，以确定妇女的风险增加，并澄清与绝经后激素治疗相关的乳腺癌风险。 公共卫生相关性：非常需要确定患乳腺癌风险增加的妇女。申请人使用深入的定量技术对血液中的循环蛋白进行分析以确定潜在风险标志物的先前研究已经在随后发展为乳腺癌的绝经后妇女中鉴定了许多潜在的风险标志物。这些新的乳腺癌候选风险标志物需要额外的研究来验证。本提案的目的是在来自妇女健康倡议的一组独立妇女中对候选生物标志物进行额外的验证研究，并确定这些标志物作为绝经后激素治疗相关乳腺癌风险介质的相关性。

DESCRIPTION (provided by applicant): There is a substantial need to identify biomarkers of risk for breast cancer. An in-depth quantitative proteomics approach was applied to the analysis of plasmas that were collected prior to a diagnosis of breast cancer in search for candidate markers of risk for this disease. The samples were obtained from the Women's Health Initiative (WHI) cohort and consisted of women diagnosed with breast cancer within seven years of blood collection and controls matched for age, self-reported ethnicity, hysterectomy status and enrollment date. In parallel studies proteomic profiling was applied to blood specimens obtained at baseline and following one year of hormone therapy (HT) with conjugated equine estrogen (CEE) or CEE/MPA (medroxyprogesterone acetate). Extensive proteomic analyses identified a large subset of circulating proteins that were affected by HRT, and has also yielded a set of breast cancer risk marker candidates that merit additional validation studies. Interestingly some of the risk candidates were also affected by HRT and thus may contribute to elucidation of breast cancer risk associated with CEE/MPA therapy. In aim 1, we propose to conduct a confirmation study of risk markers identified using an independent set of WHI participants from the WHI hormone therapy trials who developed breast cancer and matched controls. Of the 14 candidates to be subjected to confirmation studies, eight have ELISAs available that would allow their assay. The remainder of the candidates would be subjected to confirmation using Multiple Reaction Monitoring mass spectrometry. A second aim consists of evaluating the identified risk markers as mediators of hormone therapy effects on breast cancer. To that effect plasmas collected at baseline and at 1-year of HT in the CEE and CEE/MPA trials will be utilized to determine changes in concentration of risk marker candidates in cases and in matched controls. The proposed project has the potential to contribute clinically relevant breast cancer biomarkers to identify women at increased risk and to clarify breast cancer risk associated with postmenopausal hormone therapy. PUBLIC HEALTH RELEVANCE: There is a substantial need to identify women at increased risk for developing breast cancer. Prior studies by the applicants using in-depth quantitative technology to profile circulating proteins in the blood for potential risk markers have identified many potential markers of risk among post-menopausal women that subsequently developed breast cancer. These novel candidate risk markers for breast cancer require additional studies for their verification. The objectives of this proposal to do additional verification studies of the candidate biomarkers in an independent set of women from the Women's Health Initiative and to determine the relevance of these markers as mediators of the risk for breast cancer associated with post-menopausal hormone therapy.