Candidate treatments of brain metastases suggested fromin silico gene expression analysis of archival primary breast tumor tissue and brain metastases (BM)

Abstract

e22203 Background: Patients with metastatic breast cancer are living longer due to advances in therapy. Interestingly, there are times when systemic disease is well controlled but progression continues within the central nervous system (CNS). We report our retrospective analysis of gene expression data from the GEO database. Methods: We interrogated the NCBI/GEO database using the following search terms: breast cancer, gene expression, and brain metastases. We identified a set of tissue samples and compared gene expression arrays from 4 separate BM specimens to 7 primary breast cancer specimens; all specimens were Her-2 neu +/ER - tumors except one (information unavailable). Using a t-test, a two-fold or greater change in gene expression was considered significant if the p-value was <0.05. Results: Analysis of the gene expression profiles revealed several gene candidates over expressed in the BM specimens as compared to primary tumor specimens. Of interest are the motility-associated genes (ICAM1, cortactin, DOCK11, and myosin; p<0.03), pro-survival gene (AKT3; p<0.03), the FGF-growth factor signaling pathway (FGF1; p<0.02), and genes positively regulating the epithelial-to-mesenchymal transformation (EMT) process [TGFB1, SNAI2 (SLUG), NOTCH2; p<0.03]. Notably, the TGFB/Slug pathway is influenced by Sonic hedgehog (SHH). SHH inhibitors are currently being investigated in phase I clinical trials. Conclusions: To the best of our knowledge, this is the first analysis to suggest a role for TGFB and SHH signaling as it relates to the metastatic potential of breast cancer. Our findings argue for gene expression analysis on a larger number of BM specimens for discovery and validation of gene candidates important for this malignant progression. As there are drugs already available to target these pathways, the goal would be to accrue more patients with primary or secondary CNS malignancies to assess response. No significant financial relationships to disclose.