A unique approach combining avatar mice and targeted mass spectrometry to identify blood biomarkers for early detection of breast cancer

一种独特的方法，结合阿凡达小鼠和靶向质谱分析来识别血液生物标志物，以早期检测乳腺癌

• 批准号: 10462864
• 负责人: Michael T. Lewis
• 金额: $ 18.78万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462864
• 关键词: Animals; Benign; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Breast; Breast Cancer Detection; Breast Cancer Early Detection; Cancerous; Case-Control Studies; Clinical; Collection; Complement; Data Set; Diagnosis; Disease; ERBB2 gene; Early Detection Research Network; Early Diagnosis; Ensure; Enzyme-Linked Immunosorbent Assay; Estrogen receptor positive; Failure; Funding; General Population; Genomics; Goals; Guidelines; Human; Individual; Isotopes; Lesion; Life; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammographic screening; Mammography; Maps; Mass Spectrum Analysis; Methodology; Mucin 1 protein; Mus; Neoplasm Transplantation; Noninfiltrating Intraductal Carcinoma; Patients; Peptides; Performance; Phase; Plasma; Procedures; Proteins; Proteomics; Research Design; Sampling; Savings; Screening for cancer; Sensitivity and Specificity; Shotguns; Specificity; Testing; The Cancer Genome Atlas; Tissues; Training; Transplantation; Triage; Tumor Markers; Ultrasonography; Validation; Woman; Xenograft procedure; base; biomarker panel; blood-based biomarker; breast lesion; cancer biomarkers; cancer site; candidate marker; candidate validation; case control; circulating biomarkers; clinical diagnostics; early detection biomarkers; early screening; human tissue; improved; malignant breast neoplasm; mortality; multiple reaction monitoring; multiplex assay; novel; novel marker; novel strategies; patient population; population based; predictive modeling; protein biomarkers; screening; screening guidelines; screening program; success; tumor

Project Summary/Abstract Tens of millions of women undergo population-based screening for breast cancer by mammography. De- spite the life-saving potential of early detection, screening guidelines for mammography are controversial and continue to evolve. At issue are the specificity of mammography for distinguishing benign vs cancerous le- sions, the sensitivity of mammography in some patient populations (e.g. women with dense breasts), and con- cerns regarding over-diagnosis (e.g. some ductal carcinoma in situ). Our ultimate clinical aim is to develop a blood test for early detection of breast cancer that can be used in conjunction with mammography to improve sensitivity and specificity during screening, and thus have enormous clinical impact by detecting treatable can- cers missed by mammography (reducing mortality) and by avoiding unnecessary invasive procedures for be- nign or non-life-threatening disease. Despite considerable effort, attempts to identify blood-based screening biomarkers for early detection of breast cancer have failed, due to technological and methodological limitations. Clearly new approaches are warranted. We are proposing a completely novel strategy, based on the initial discovery of candidate bi- omarkers in the plasma of “avatar mice” (harboring early passage human breast cancer xenografts), and fol- lowed by biomarker triage and validation using a novel biomarker pipeline based on a targeted form of mass spectrometry (MS), multiple reaction monitoring (MRM). If successful, this study could provide a road map for applying this general approach to other cancer sites, beyond breast cancer. Briefly, candidate circulating biomarkers identified in the avatar mouse plasma will be verified in the plasma from the human patients and prioritized for further testing based on integrative proteo-genomic analyses using large breast cancer datasets generated by NCI genomic and proteomic consortia (TCGA and CPTAC). A nov- el, multiplex MRM-based assay will be developed and analytically validated (according to established fit-for- purpose guidelines) to quantify up to 50-100 prioritized biomarker candidates. Candidate biomarkers will be evaluated in an existing, strongly unbiased collection of plasma samples in which plasmas were collected prior to biopsy, compliant with PRoBE study design criteria, under an SOP from women with undiagnosed mammo- graphic lesions. Performance of the candidate biomarkers will initially be assessed in a training set (100 cas- es, 100 controls) to verify which candidates show a mean difference in plasma levels between cases vs con- trols, and to test the possibility of building a multiple marker prediction model. Subsequently, individual candi- date biomarkers (as well as a potential multiple marker prediction model) will be assessed in an independent validation set (150 cases, 150 controls) to estimate the sensitivity and specificity of the markers/panel.

项目概要/摘要 数以千万计的女性通过乳房X光检查接受基于人群的乳腺癌筛查。德- 尽管早期检测具有挽救生命的潜力，但乳房 X 光检查的筛查指南仍存在争议，并且 继续发展。问题在于乳房X线照相术区分良性和癌性病变的特异性。 一些患者群体（例如乳房致密的女性）的乳房 X 光检查的敏感性，以及 关于过度诊断的担忧（例如一些导管原位癌）。我们的最终临床目标是开发一种 用于早期发现乳腺癌的血液检测，可与乳房 X 光检查结合使用以改善乳腺癌 筛选期间的敏感性和特异性，因此通过检测可治疗的癌症具有巨大的临床影响 通过乳房X光检查（降低死亡率）和避免不必要的侵入性手术来发现漏掉的cers 恶性或不危及生命的疾病。 尽管付出了巨大的努力，但仍尝试识别基于血液的筛查生物标志物以进行早期检测 由于技术和方法的限制，乳腺癌已经失败。显然，新方法是 保证。我们正在提出一种全新的策略，基于候选双的初步发现 “阿凡达小鼠”（携带早期传代人类乳腺癌异种移植物）血浆中的标记物，以及 使用基于目标质量形式的新型生物标志物管道进行生物标志物分类和验证 光谱分析 (MS)、多反应监测 (MRM)。如果成功的话，这项研究可以提供一个路线图 将这种通用方法应用于乳腺癌以外的其他癌症部位。 简而言之，在阿凡达小鼠血浆中识别出的候选循环生物标志物将在血浆中进行验证 来自人类患者，并根据综合蛋白质基因组分析优先进行进一步测试 由 NCI 基因组和蛋白质组学联盟（TCGA 和 CPTAC）生成的大型乳腺癌数据集。一个新的 el，将开发基于多重 MRM 的测定并进行分析验证（根据已建立的适合- 目的指南）量化多达 50-100 个优先候选生物标志物。候选生物标志物将是 在现有的、非常公正的血浆样本收集中进行评估，其中血浆是事先收集的 根据 PRoBE 研究设计标准，根据 SOP 对患有未确诊乳房的女性进行活检 图形病变。候选生物标志物的性能最初将在训练集（100 个样本）中进行评估 es，100 个对照）来验证哪些候选者表现出病例与对照之间血浆水平的平均差异 控制，并测试构建多标记预测模型的可能性。随后，个人候选人 日期生物标志物（以及潜在的多标志物预测模型）将在独立的评估中进行评估 验证集（150 个病例，150 个对照）来估计标记/面板的敏感性和特异性。