Abstract 224: Novel potential precursor structures for BRCA1-associated breast cancer

Abstract

Abstract Objectives: Female individuals with BRCA1 germline mutation have an 80-90% risk to develop breast cancer during their lifetime. BRCA1 cancers are distinct from sporadic breast cancers as they more frequently show high-grade histology and are typically estrogen receptor and HER2-negative. While sporadic breast ductal carcinoma is thought to be preceded by in-situ precursors, the presence of precursors is uncertain in BRCA1 cancers. To better understand breast carcinogenesis in BRCA1 patients, we developed an approach to perform unprecedently detailed structural analysis of breast tissue. Design: A prophylactic mastectomy product of a BRCA1 patient with history of contralateral breast cancer was obtained after routine pathological evaluation then trimmed into 0.3 × 1 x1.5 cm tissue blocks (n=94). Initial sections from each block were H&E stained and microscopically evaluated. Any lobular or ductal structure with increased cellularity was recorded as hyperplastic event. Correlation of hyperplastic events on the surface of blocks and topographic information of events led to the identification of “hot” regions with larger numbers of these events. From the center of this region, the block was serially sectioned at 5μm-depth. H&E staining of every tenth section allowed a three-dimensional (3D) reconstruction of all hyperplastic events. The same procedure was applied to a normal control tissue product of a prophylactic mastectomy in a non-BRCA1 patient with personal history of contralateral breast cancer. Results: We identified five novel “isolated epithelial structures” within BRAC1 breast tissue. On a single two dimensional (2D) slide, these isolated epithelial structures resemble regular lobular and ductal structures with hyperplastic features; while after 3D reconstruction with 2D slides, they revealed in isolation from connection to regular anatomic epithelial structures and were entirely separated by mesenchymal tissue. Importantly, we report in detail an isolated tubular epithelial structure in association with an incidental millimeter-sized, BRCA1-deficient cancer focus. This structure is 2mm in length, mostly surrounded by myoepithelial cells, and remarkable for simultaneous development of lobular and ductal hyperplasia including flat epithelial hyperplasia. The transition zone into cancer is characterized by loss of myoepithelial cells and significant cytologic atypia. Conclusions: Our thorough examination of BRCA1 breast tissue allowed for the first time the identification of isolated epithelial structures. Our identification of one isolated epithelial structure in connection with the development of an infiltrating carcinoma focus strongly suggests that isolated epithelial structures are potential precursors for BRCA1 breast cancers. Analysis of these structures may lead to the discovery of new preventive and therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 224. doi:10.1158/1538-7445.AM2011-224