Molecular characteristics of matched brain metastasis (BM) versus the primary breast cancer (PBC)

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 2_Supplement; p. 2028
• Main Authors: Duchnowska, R, Jassem, J, Shen, C, Thorat, M, Li, L, Morimiya, A, Zhao, Q, Biernat, W, Mandat, T, Staszkiewicz, R, Och, W, Szostak, W, Gugala, K, Trojanowski, T, Czartoryska-Arlukowicz, B, Szczylik, C, Nakshatri, H, Steeg, P, Sledge, G, Badve, S
• Format: Journal Article
• Language: English
• Published: 15.01.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS-2028

Abstract Abstract #2028 Background: Brain is increasingly a site of relapse in breast cancer patients, however the molecular patho-physiology of this process is not well understood. Using a novel assay allowing high-throughput analysis of gene expression from formalin-fixed paraffin-embedded (FFPET) tumor samples, we compared molecular characteristics of BM with those of the PBC in a series of breast cancer patients who underwent excision of brain metastasis.
 Methods: In each patient we performed molecular analysis of paired archived FFPET specimens from both the PBC and excised BM. Of the 37 pairs of PBC/BM samples, 24 pairs had sufficient pathology material for molecular analysis. Patient characteristics: mean age at PBC diagnosis was 46.7 years (range 27-67 years); 7 (29%) ER+, 17 (71%) ER-, 12 (50%) HER2-positive(3+). We performed cDNA-mediated annealing, selection, extension and ligation (DASL) assay (Illumina Corp) for expression of 502 known cancer genes, using 200 ng RNA. Statistical analysis for microarrays (SAM) accounting for the pairing of the primary and metastasized tumors was used to identify differentially expressed genes while controlling the false discovery rate (FDR <0.01). BeadStudio™ Absolute correlation clustering was used to cluster samples based on their expression profiles.
 Results: In only 7 (29%) cases matched PBC and BM pair clustered together on unsupervised hierarchical clustering, the pairs in remaining cases clustered apart. Comparison of the two groups (PBC and BM) showed that 41 genes were up regulated in BM, including proliferation genes (CDC2, CDC25a, CCNA2 and E2F family), anti-apoptotic (BIRC5), DNA repair (RAD51, -54b, XRCC2, BRCA2, BARD1, TOP1), angiogenesis (VEGF), and development of drug resistance (ABCB1, -G2). In contrast, the 43 genes that were down regulated in BM included those associated with invasion (MMP2, -3, -14), cellular motility, and epithelial to mesenchymal transformation (CDH11). Additional analysis to validate these trends and to identify potential therapeutic targets is underway.
 Conclusions: Although some BM retain remarkable similarity to the PBC, majority exhibit considerable deviation in their gene expression profile. These “adaptive” changes include greater resistance to drug therapy, increased DNA repair, a reversal back to the epithelial phenotype and decreased capacity for cell motility and invasion. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2028.