Abstract P3-04-07: Comparison of breast tumors with HER2 amplification and polysomy 17

Abstract

Abstract Background: Approximately 20% of invasive breast cancers overexpress the human epidermal growth factor receptor, Her2, and are associated with poor prognosis including decreased relapse-free and overall survival. Overexpression of the Her2 protein is primarily due to amplification of the HER2 oncogene on chromosome 17, and these patients are typically treated with targeted therapies such as trastuzumab or lapatinib. However, increased HER2 copies may also result from chromosome 17 polysomy in which the entire chromosome has been duplicated one or more times. The clinical benefit of treating patients with polysomy 17 in the absence of HER2 amplification with targeted therapy remains unclear. Herein, we compared the clinical characteristics as well as the gene expression profiles of breast tumors with increased HER2 copy numbers due to HER2 amplification or chromosome 17 polysomy. Methods: Patients for this study were enrolled in the Clinical Breast Care Project. HER2 and CEP17 copy numbers were determined using the PathVysion HER-2 DNA Probe Kit (Abbott Laboratories). Only those patients with at least 4 HER2 copies per cell were included in the analysis; those with a HER2/CEP17 ratio <2.2 were considered polysomic (N = 29) while those with a ratio >2.2 (N = 44) were considered amplified. Microarray data were generated on HG U133A 2.0 arrays (Affymetrix) for those samples with tissue available (14 polysomy and 18 amplified cases) and analyzed using Partek Genomics Suite. Results: Tumor grade and size did not differ between polysomic and amplified samples. Although amplified cases tended to be younger at diagnosis and less likely to be diagnosed with Stage I tumors, this difference did not reach statistical significance. HER2 amplified tumors were more likely to be ER negative (P = 0.027) and have lymph node metastases (P = 0.028) than polysomic tumors. Comparison of polysomic and amplified cases by expression microarray identified 67 genes that were differentially expressed (P < 0.01; fold change >2) between the two groups. Thirty-nine genes were more highly expressed and 28 genes more lowly expressed in tumors with HER2 gene amplification when compared to tumors from patients with chromosome 17 polysomy. Discussion: ER and lymph node status of breast tumors from women with increased HER2 copy number differed depending on whether the increased copy number was due to HER2 gene amplification or conversely, polysomy of chromosome 17. Likewise, gene expression profiles also differed depending on whether increased HER2 was due to gene amplification or chromosomal gain. Those genes with significant levels of differential expression between these two groups are involved in cell cycle control, cell adhesion and migration, cell differentiation, cytoskeleton organization, signal transduction, protein synthesis and degradation, and ion transport. Interestingly, the top 4 most significant genes with higher expression in the polysomic samples, including TUBG1, CPD, BLMH, and JUP, are all located on 17q. Currently, it is not clear whether treatment with targeted Her2 therapy is beneficial in patients with chromosome 17 polysomy. However, the genes identified here may represent novel targets for developing new treatments that are effective in these women and require further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-07.