Abstract LB-278: Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component

Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma. Metaplastic breast carcinoma is a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as a clonal outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact in these samples, without having matched normal tissue. We then determined the genetic relationships between the histologically distinct compartments. In each case, the tumor components have nearly identical landscapes of somatic variation, implying that the differing histologies do not derive from genetic clonal divergence, suggesting that epigenetic or noncoding changes mediate the metaplastic phenotype. This indicates that alternative therapeutic approaches, including epigenetic therapies, may render metaplastic breast cancers susceptible to current and future therapies. Citation Format: Bracha E. Avigdor, Katie Beierl, Christopher D. Gocke, Daniel J. Zabransky, Karen Cravero, Kelly Kyker-Snowmana, Berry Button, David Chu, Sarah Croessmann, Rory L. Cochran, Roisin M. Connolly, Ben H. Park, Ashley Cimino-Mathews, Sarah J. Wheelan. Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2017-LB-278