CONFIRMATION STUDIES OF BLOOD BASED BIOMARKERS OF RISK FOR BREAST CANCER

描述(由申请人提供)：有大量需要确定乳腺癌风险的生物标记物。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，以寻找这种疾病的候选风险标记。样本来自妇女健康倡议(WHI)队列，包括在采血七年内被诊断患有乳腺癌的妇女和与年龄、自我报告的种族、子宫切除状况和登记日期匹配的对照组。在平行研究中，蛋白质组图谱被应用于基线和激素治疗(HT)一年后的血液样本，用结合马雌激素(CEE)或CEE/MPA(甲羟孕酮醋酸酯)治疗。广泛的蛋白质组学分析确定了受HRT影响的循环蛋白的一大子集，并产生了一组值得进行额外验证研究的乳腺癌风险标记候选。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，我们建议对风险标记物进行确证研究，使用来自WHI激素治疗试验的一组独立的WHI参与者，他们发展为乳腺癌和匹配的对照组。在14名将接受确认研究的候选人中，有8名拥有允许他们进行分析的ELISA。其余的候选人将接受多反应监测质谱学的确认。第二个目标是评估已确定的风险标记物作为乳腺癌激素治疗效果的中介。为此，将利用在CEE和CEE/MPA试验中在HT基线和一年时收集的血浆来确定病例和匹配对照中风险标记物候选浓度的变化。拟议的项目有可能贡献临床相关的乳腺癌生物标记物，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。 与公共卫生相关：有必要确定罹患乳腺癌风险增加的妇女。申请者之前的研究使用深入的定量技术来分析血液中循环蛋白的潜在风险标记物，已经在绝经后妇女中发现了许多随后发展为乳腺癌的潜在风险标记物。这些新的乳腺癌候选风险标记物需要额外的研究来验证它们。这项提议的目的是对妇女健康倡议的一组独立女性的候选生物标记物进行额外的验证性研究，并确定这些标记物作为绝经后激素治疗相关乳腺癌风险的介体的相关性。

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.