Development of a blood test for breast cancer detection

开发乳腺癌检测血液检测方法

• 批准号: 7536369
• 负责人: Richard Idem Somiari
• 金额: $ 10万
• 依托单位: INTEGRATED TECHNOLOGIES & SRVCS INTRNTL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536369
• 关键词: Benchmarking; Benign; Biological Assay; Biological Markers; Blood; Blood Tests; Breast Cancer Detection; Breast Diseases; Cancerous; Categories; Classification; Clinic; Complement; DNA Microarray Chip; DNA Microarray format; Data; Data Analyses; Detection; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Early Diagnosis; Evaluation; Female; Health Care Costs; Healthcare; Housekeeping Gene; Individual; Lesion; Malignant - descriptor; Malignant Neoplasms; Mammography; Measures; Medically Underserved Area; Methods; Modeling; Morbidity - disease rate; Nonparametric Statistics; Operative Surgical Procedures; Outcome; Patients; Pattern; Performance; Phase; Probability; Public Health; RNA; RNA Probes; RNA analysis; Range; Receiver Operator Characteristics; Relative (related person); Reporting; Running; Rural; Sampling; Screening procedure; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Specimen; Staging; Technology; Testing; Time; Translations; Travel; Tube; Validation; Woman; base; breast lesion; design and construction; expectation; interest; malignant breast neoplasm; medically underserved population; mortality; performance tests; prototype; tool

DESCRIPTION (provided by applicant): Mammography is the benchmark for breast disease detection and diagnosis. However, it can miss 10-15% of early stage breast cancers, and it is unable to distinguish between benign and malignant lesions with certainty. Availability of an alternate method e.g. biomarker based, which allows early detection/precise distinction between benign disease and breast cancer will reduce mortality associated with breast cancer. We previously used DNA microarrays to screen >300 blood RNA specimens, and identified 24 RNA signatures that allowed precise identification of selected patients with breast disease. Based on the prospect of commercializing the identified biomarkers as a blood-based test for breast disease detection, we propose to validate the candidate biomarkers using a platform that is more amenable to translation into the clinic. Objective: To develop a biomarker based blood test for breast disease detection and classification. The specific aims of the project are: 1) design and construct QuantiGene probes for multiplexed blood RNA analysis, 2) test the probes with blood RNA samples, and develop a prototype classification model for identification of individuals with benign breast disease (BD) and breast cancer (BC) and 3) validate the performance of the prototype model in identifying donor categories. Methods: QuantiGene RNA probes targeting 24 biomarkers of interest and 3 housekeeping genes will be designed and constructed. Blood will be collected with PAXGene RNA stabilization tubes, from female donors (>21y) classified as normal (n=30), with BD (n=30) and BC (n=30), and screened with the QuantiGene probes. Data will be normalized with the best housekeeping gene and analyzed. Then, a prototype classification model will be developed and validated using new samples collected from additional normal (n=10), BD (n=10) and BC (n=10) donors. Data analysis: Descriptive, graphical and non-parametric statistics will be performed to determine the pattern and significance of expression of the biomarkers. The prototype classification model will be evaluated by calculating performance evaluation measures (sensitivity, SN; specificity, SP; and accuracy), to distinguish between high-performance classifiers and the null expectation of no significant classifier. SN and SP values will be reported across a range of decision rules to generate the receiver operator characteristics (ROC). We will also assess; a) detection sensitivity, b) assay range, c) precision, d) relative accuracy and fold-change correlations among the variables. Expected outcome: If successful, the proposed blood test will augment mammography, produce faster results, reduce the time a patient has to wait before getting a conclusive diagnosis and allow screening to be performed remotely. In the long run, such a test will reduce patient mortality/morbidity and overall healthcare cost. PUBLIC HEALTH RELEVANCE:Although mammography is still the best tool for screening and detection of breast disease, it can miss 10-15% of early stage cancers and it is unable to differentiate between benign and malignant lesions with certainty. We propose to develop a blood based test that will complement/augment mammography, produce faster and more objective results, reduce the time a patient has to wait before getting a conclusive diagnosis and allow many more women including those in rural and medically underserved areas to routinely test for breast cancer. The health care benefit of this test will include reduced morbidity/mortality and overall healthcare cost/burden due to breast cancer.

描述（由申请人提供）：乳房x光检查是乳房疾病检测和诊断的基准。然而，它可能会遗漏10-15%的早期乳腺癌，并且无法确定区分良性和恶性病变。如果有一种替代方法，例如基于生物标志物的方法，可以早期发现/精确区分良性疾病和乳腺癌，将减少与乳腺癌相关的死亡率。我们之前使用DNA微阵列来筛选bbb300个血液RNA样本，并确定了24个RNA特征，可以精确识别选定的乳腺疾病患者。基于将已确定的生物标志物商业化作为乳腺疾病检测的血液检测的前景，我们建议使用更易于转化为临床的平台来验证候选生物标志物。目的：建立一种基于生物标志物的乳腺疾病血液检测方法。该项目的具体目标是：1)设计和构建用于血液RNA多路分析的QuantiGene探针；2)用血液RNA样本对探针进行测试，并开发用于识别乳腺良性疾病（BD）和乳腺癌（BC）个体的原型分类模型；3)验证原型模型在识别供体类别方面的性能。方法：设计和构建针对24个感兴趣的生物标志物和3个管家基因的QuantiGene RNA探针。血样将用PAXGene RNA稳定管采集，血样来自女性献血者（bb0 ~ 21y），分为正常（n=30）、BD （n=30）和BC (n=30)，并用QuantiGene探针筛选。数据将用最佳管家基因进行归一化并进行分析。然后，将开发一个原型分类模型，并使用从额外的正常（n=10）、BD （n=10）和BC （n=10）供体中收集的新样本进行验证。数据分析：将进行描述性、图形性和非参数性统计，以确定生物标志物表达的模式和意义。将通过计算性能评价指标（灵敏度、SN、特异性、SP和准确性）对原型分类模型进行评估，以区分高性能分类器和无显著分类器的零期望。SN和SP值将在一系列决策规则中报告，以生成接收器操作员特征（ROC）。我们也会评估；A)检测灵敏度，b)测定范围，c)精密度，d)相对准确度和变量之间的倍数变化相关性。预期结果：如果成功，拟议的血液检查将增强乳房x光检查，产生更快的结果，减少患者在获得结结性诊断之前的等待时间，并允许远程进行筛查。从长远来看，这种测试将降低患者死亡率/发病率和总体医疗保健成本。公共卫生相关性：尽管乳房x光检查仍然是筛查和检测乳腺疾病的最佳工具，但它可能会遗漏10-15%的早期癌症，并且无法确定区分良性和恶性病变。我们建议开发一种基于血液的检查，以补充/增强乳房x光检查，产生更快、更客观的结果，减少患者在得到结结性诊断之前的等待时间，并允许更多妇女（包括农村和医疗服务不足地区的妇女）进行乳腺癌常规检查。这项检测的保健益处将包括降低乳腺癌的发病率/死亡率和总体保健费用/负担。