CONFIRMATION STUDIES OF BLOOD BASED BIOMARKERS OF RISK FOR BREAST CANCER

描述（由申请人提供）：确实需要确定乳腺癌风险的生物标志物。深入定量蛋白质组学方法应用于分析乳腺癌诊断前收集的血浆，以寻找该疾病风险的候选标记物。样本来自妇女健康倡议（WHI）队列，包括7年内被诊断患有乳腺癌的妇女，并与年龄、自我报告的种族、子宫切除术状态和登记日期相匹配的对照。在平行研究中，蛋白质组学分析应用于基线和使用结合马雌激素（CEE）或CEE/MPA（醋酸甲孕酮）进行激素治疗（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影响的大量循环蛋白，并且还产生了一组值得进一步验证研究的乳腺癌风险标记候选物。有趣的是，一些风险候选者也受到激素替代疗法的影响，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，我们建议进行一项风险标记的确认研究，使用一组来自WHI激素治疗试验的患乳腺癌的WHI参与者和匹配的对照。在接受确认研究的14个候选药物中，有8个有可用的酶联免疫吸附试验（elisa）。其余的候选者将使用多重反应监测质谱法进行确认。第二个目标包括评估已确定的风险标记作为激素治疗对乳腺癌影响的媒介。为此，在CEE和CEE/MPA试验中基线和1年HT时收集的血浆将用于确定病例和匹配对照中风险标记候选物浓度的变化。拟议的项目有可能提供临床相关的乳腺癌生物标志物，以识别风险增加的妇女，并澄清与绝经后激素治疗相关的乳腺癌风险。

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.