PROJECT SUMMARY/ABSTRACT The Biospecimen and Pathology Core of the Mayo Clinic Breast Cancer SPORE provides an expert centralized pathology consultative service and a comprehensive resource of breast tissues, blood and “living samples” for preparation of organoids and patient-derived xenografts, linked to epidemiological and clinical data. The Core also curates clinically derived benign and neoplastic breast tissue samples with detailed clinicopathological evaluation (e.g., stage, histologic features, clinical and emerging biomarker assessments) to establish registries and cohorts for research. Samples collected include fresh, fresh-frozen, cryopreserved and formalin-fixed paraffin embedded specimens from 1) treated or untreated breast cancers with mapped background “benign-adjacent” tissues, 2) lymph node metastases and distant metastases, 3) benign breast disease tissues across the spectrum of pre-neoplasia and 4)“normal” breast tissue harvested from mammoplasty/risk reduction specimens from patients with or without clinical or genetic “high-risk” factors (e.g. known germline BC predisposition gene mutations), as well as blood. The Core performs expert pathological evaluation of research- related histopathological parameters (e.g., atypia in benign breast disease, involution status of breast lobules, histologic subclassification of TNBC, evaluation of tumor response to neoadjuvant therapy, stromal and intratumoral TIL scoring). In addition, the Core performs antibody optimizations as required by the SPORE projects (e.g. PKCBeta1), followed by interpretation and scoring of these immunohistochemical stains, and application of digital image-based approaches (e.g., optimization and interpretation of digital image analysis algorithms with Aperio (Leica) (or HALO (Indica Labs) software systems, high-plex quantitative digital spatial profiling (e.g. Nanostring GeoMX™ platform) for SPORE projects. The Core coordinates with the Mayo Biospecimen Accessioning and Processing (BAP) Shared Resource to store fresh-frozen and cryopreserved specimens and to process blood samples to provide genomic DNA and serum and plasma aliquots; it collaborates with the Mayo Pathology Research Core (PRC) Shared Resource to obtain essential technical tissue-based services including conventional and cryostat tissue sectioning, immunohistochemistry, tissue microarray construction, slide scanning and cytotechnologist assistance for optimizing digital imaging algorithms. Partnering with these institutional shared resources minimizes redundancy of services and capitalizes both on technical experience and state-of-the-art technologies.