HER2 gene amplification is a marker for global genomic instability

Abstract

9571 Background: Genomic alterations of the proto-oncogene c-erbB-2 (HER2/neu) are associated with poor prognosis in patients with breast cancer. While HER2 status has predictive value for the efficacy of different therapies, its long-term prognostic relevance remains controversial. Because some patients with HER-2 gene amplification do not exhibit corresponding over-expression of the HER-2 protein, it is unclear how genomic alterations predict clinical response. To assess the implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER-2 status in patients with invasive breast cancer. Methods: DNA was extracted after laser microdissection from 75 paraffin-embedded invasive breast tumor specimens, 24% of which had HER-2 amplification determined by the PathVysion FISH assay. Referent DNA was extracted from blood, disease-free skin, or negative lymph node samples. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly deleted in breast cancer. The threshold normalized peak height ratio to detect AI was set at 0.35 and t-tests were used to investigate relationships between genomic instability and HER-2 status. Results: Overall levels of AI did not differ significantly in patients stratified by stage, lymph node, or menopausal/hormonal status. The frequency of AI was significantly higher (P<0.001) however, in patients with HER-2 amplification (39%) compared to those without (21%). When individual chromosomal regions were examined, samples with HER-2 amplification showed significantly higher levels of AI (P<0.0001at chromosome 17q12 (which is located <5 Mb centromeric to the HER-2 locus and includes BRCA1), as well as chromosomes 17p13.1 and 22q12.3 (P<0.05). Conclusions: HER-2 gene amplification may serve as a marker of global genomic instability. Concurrent genetic alterations in other regions of the genome may contribute to poor prognosis and influence associations between HER-2 status and outcomes of adjuvant chemotherapy and Herceptin treatment. The addition of molecular profiling for AI may thus enhance treatment decisions for individuals with HER-2 amplified breast cancer. No significant financial relationships to disclose.