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

项目总结/摘要（总体组件，RFA-CA-22-040） 我们建议开发一种基于血液的测试，其指示用途是在早期补充乳房X光检查。 检测乳腺癌。虽然乳房X光检查可以通过早期发现挽救生命，但它并不完美。 大约七分之一的乳腺癌在筛查性乳房X光检查中未被发现， 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烦恼的问题，特别是（尽管不是） 专门）用于美国> 2700万具有不均匀或极致密乳房的女性， 患间歇性癌症的风险很高。我们建议开发一种血液测试，可以作为辅助手段， 乳腺X射线摄影术，以通过提高乳腺X射线摄影术的灵敏度和/或特异性来提高早期检测。使用 利用人鼠乳腺癌患者来源的异种移植物的新生物标志物发现方法 模型和最先进的质谱分析方法，我们优先考虑了162个候选乳腺癌蛋白 生物标志物用于验证研究。 我们的BCC将对我们优先考虑的162份候选血浆进行EDRN第2阶段生物标志物验证研究 乳腺癌的蛋白质生物标志物。我们拥有一支经验丰富的多学科团队（包括两名初级 研究者），具有良好的生产合作记录，并代表临床专业知识 肿瘤学、癌症生物标志物、病理学、CLIA/CAP/GLP测定、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学。我们的团队包括2个行业合作伙伴， 3个CLIA实验室，可提供专业知识并访问CLIA/CAP/GLP中的多个定量平台 环境，以支持EDRN网络合作，与其他BCC进行生物标志物验证研究。 生物标志物开发实验室将通过以下方式为生物标志物验证研究做出贡献： 用于定量162种候选蛋白质生物标志物的合格试剂和方法，（ii）获取血浆 生物样本（符合EDRN PRoBE研究设计），用于2期生物标志物验证研究，（iii） 以盲态方式向我们的BRL CLIA实验室提供血浆等分试样，以及（iv）分析EDRN第2阶段验证 由BRL生成的数据，提供统计，流行病学和乳腺成像专业知识， 评估性能指标，以确保生物标志物足以提供早期检测的临床实用性。 生物标志物参考实验室将通过以下方式促进拟议的验证研究：（i）验证CLIA- 用于定量多达162种候选蛋白质的免疫MRM测定的合规标准操作规程 早期乳腺癌的生物标志物，将作为我们的生物标志物验证研究的基础，（ii） 进行第2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测定。 行政核心将支持BCC的所有方面，包括管理所有行政和项目 管理BCC的各个方面，以及管理所有中心的物流和通信。

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.