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

(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 CLIAcompliant 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.