Abstract 4988: Clues for targeted therapies in inflammatory breast cancer (IBC)

Abstract

Abstract Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development, and poor prognosis. The peculiar clinical presentation of IBC characterized by breast erythema and swelling is caused by the invasion of aggregates of tumor cells (tumor emboli) into the dermal lymphatics, causing an obstruction of the lymph channels. Although, tumor emboli are also occasionally demonstrated in non-IBC tumors, they are more frequently detected and more numerous in IBC. Tumor emboli expressed cell-cell adhesion molecules that maintain the tumor cells together. The high risk of disease recurrence in soft tissue and lymph nodes shortly after completion of multidisciplinary treatment particularly in patients with residual disease supports the hypothesis that these tumor emboli are critically related to the development of micro metastatic disease. We developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters in suspension that were strongly positive for E-cadherin, β-catenin, and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. The maintenance of cell-cell adhesions allow the migration of tumor cells through the lymphatic and blood vessels as clusters. FC-IBC02 cells shown a partial or incomplete epithelial-mesenchymal transition (EMT); these cells express some epithelial markers (EpCAM, E-cadherin) and also mesenchymal markers (VIM, FN1, Snai2, Twist1). Furthermore, circulating tumor cells (CTC) from IBC patients are present in the blood as single cells and clusters supporting the collective migration of tumor cells in IBC. FC-IBC02 cells were highly metastatic when injected in the fat mammary pad of SCID mice and these cells were able to produce brain metastasis in mice by intracardiac or intra-peritoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5-7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6-4 copies in IBC cells. FAK1 is amplified, upregulated and phosphorylated (active) in inflammatory breast cancer. Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. Our results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC. We are currently evaluating an ALK/FAK inhibitor using the novel established IBC model. Citation Format: Sandra V. Fernandez, Fredika M. Robertson, Sankar Addya, Zhaomei Mu, Massimo Cristofanilli. Clues for targeted therapies in inflammatory breast cancer (IBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4988. doi:10.1158/1538-7445.AM2014-4988