Breast-cancer focused biomarker characterization center employing targeted mass spec assays in a CLIA environment

项目摘要/摘要(总体部分，RFA-CA-22-040) 我们建议开发一种基于血液的测试，其指定用途是补充早期的乳房X光检查。 乳腺癌的检测。虽然乳房X光检查通过早期发现拯救了生命，但它并不完美。 大约七分之一的乳腺癌在筛查乳房X光检查后仍未被发现，而且间隔时间 在正常乳房X光检查后一年内出现的癌症仍然是一个令人头疼的问题，尤其是(尽管不是 独家)针对美国2700万拥有异质或极致密乳房的女性 间歇性癌症的高风险。我们建议开发一种血液测试，可以作为辅助手段 乳房X光检查通过提高乳房X光检查的敏感度和/或特异度来改进早期检测。使用 利用人-鼠乳腺癌患者来源的异种移植发现生物标记物的新方法 模型和最新的质谱学方法，我们优先选择了162个候选乳腺癌蛋白 用于验证研究的生物标记物。 我们的BCC将对我们优先考虑的162个候选血浆进行EDRN第二阶段生物标记物验证研究 乳腺癌的蛋白质生物标志物。我们有一支经验丰富的多学科团队(包括两名初级 研究人员)具有良好的生产性协作记录并代表临床专业知识 肿瘤学，癌症生物标记物，病理学，CLIA/CAP/GLP分析，流行病学，放射学/乳腺成像， 癌症筛查、组学数据生成和生物统计。我们的团队包括2个行业合作伙伴，包括 3个CLIA实验室，可以在CLIA/CAP/GLP中提供专业知识和访问多个定量平台 支持EDRN网络与其他BCC进行生物标记物验证研究的环境。 生物标记物开发实验室将通过以下方式对生物标记物验证研究作出贡献：(I)开发 GB/T14949.7-1993合格试剂162个候选蛋白质生物标志物的定量方法(Ii)采集血浆 生物标记物验证研究的生物标记物(符合EDRN探针研究设计)，(Iii) 以盲目方式向我们的BRL CLIA实验室提供血浆等分，以及(Iv)分析EDRN阶段2验证 由BRL生成的数据，提供统计、流行病学和乳房成像专业知识以设置和 评估绩效指标，以确保生物标志物足以为早期发现提供临床实用。 生物标记参考实验室将通过以下方式为拟议的验证研究做出贡献：(I)验证CLIA- 用于定量多达162个候选蛋白质的免疫-MRM分析的符合标准的操作程序 早期乳腺癌的生物标记物，将作为我们生物标记物验证研究的基础，(Ii) 进行第二阶段生物标志物验证研究；以及(Iii)为EDRN提供参考实验室支持 网络(例如，质谱分析、流式细胞术、NextGen测序和ELISA法)。 行政核心将支持BCC的所有方面，包括管理所有行政和项目 BCC的管理方面，以及管理所有中心的物流和沟通。

Project Summary/Abstract (Overall Component, RFA-CA-22-040) We propose to develop a blood-based test whose indicated use is to complement mammography in the early detection of breast cancers. Although mammography saves lives through early detection, it is imperfect. Approximately one in seven breast cancers goes undetected despite screening mammography, and interval cancers that manifest within a year of a normal mammogram remain a vexing problem, especially (although not exclusively) for the >27 million women in the United States with heterogeneously or extremely dense breasts at high risk for interval cancers. We propose to develop a blood test that could be used as an adjunct to mammography to improve early detection by improving sensitivity and/or specificity of mammography. Using a novel biomarker discovery approach leveraging human-in-mouse breast cancer patient-derived xenograft models and state-of-the-art mass spectrometry methods, we prioritized 162 candidate breast cancer protein biomarkers for validation studies. Our BCC will perform EDRN Phase 2 biomarker validation studies of our prioritized 162 candidate plasma protein biomarkers of breast cancer. We have an experienced multidisciplinary team (including two junior investigators) with a strong track record of productive collaboration and representing expertise in clinical oncology, cancer biomarkers, pathology, CLIA/CAP/GLP assays, epidemiology, radiology/breast imaging, cancer screening, ‘omics data generation, and biostatistics. Our team includes 2 industry partners, encompasses 3 CLIA laboratories, and can provide expertise and access to multiple quantitative platforms in a CLIA/CAP/GLP environment to support EDRN Network Collaborations for biomarker validation studies with other BCCs. The Biomarker Development Laboratory will contribute to the biomarker validation studies by: (i) developing qualified reagents & methods for quantifying 162 candidate protein biomarkers, (ii) procuring plasma biospecimens (compliant with EDRN PRoBE study design) for phase 2 biomarker validation studies, (iii) delivering plasma aliquots to our BRL CLIA labs in a blinded fashion, and (iv) analyzing EDRN phase 2 validation data generated by the BRL, providing statistical, epidemiological, and breast imaging expertise to set and evaluate performance metrics to ensure biomarkers are adequate to provide clinical utility for early detection. The Biomarker Reference Laboratory will contribute to the proposed validation studies by: (i) validating a CLIA- compliant standard operating procedure for an immuno-MRM assay to quantify up to 162 candidate protein biomarkers of early-stage breast cancer that will serve as the basis for our biomarker validation studies, (ii) performing phase 2 biomarker validation studies, and (iii) providing reference laboratory support for the EDRN network (e.g., mass spectrometric analyses, flow cytometry, NextGen sequencing and ELISA assays. The Administrative Core will support all aspects of the BCC, including managing all administrative and project management aspects of the BCC as well as managing all center logistics and communication.