Abstract Introduction: Over-expression of the HER2/neu oncogene is associated with poorer clinical outcome in breast cancer. Notwithstanding the success achieved with Trastuzumab in treating HER2/neu positive patients, numerous questions remain. In particular, there are concerns regarding accurate identification of HER2/neu positivity and the correct management of these patients in terms of the dosage, timing and optimal combination of Trastzumab with chemotherapeutic regimens. One approach to answering these questions has been to focus on the area of chromosome 17 in which HER2/neu is located in order to identify other genes in the vicinity. As potential therapeutic targets, we examined the amplification and expression patterns of co-localised cancer-associated genes at the HER2/neu amplicon on chromosome 17.Aims: The primary objective of this study was to examine amplification and expression patterns of co-localised genes at 17q12-21. In doing so, we aimed to establish their relationship with HER2/neu positivity, and then to quantify their relative importance in developing a gene panel predictive of HER2/neu status.Methods: Breast tissue from a cohort of patients with HER2/neu positive (n=48) and negative (n=48) tumours was retrieved at time of surgery. Protein and gene expression levels were determined using immunohistochemistry and RQ-PCR, respectively. Results were analysed to detect patterns of amplification among the genes, namely HER2/neu, STARD3, GRB7, TOP2A, TUBG1, RPL19, LASP1, RARA, and ER Alpha, and to identify associations between expression levels and clinical data. A binary logistic approach and classification tree analysis was employed to determine whether the expression levels of our target genes were useful predictors of HER2/neu status.Results: Strong correlation was noted between expression levels of HER2/neu and multiple cancer-associated genes at 17q12-21, including the novel genes LASP1 (p=0.000) and RPL19 (p=0.000). A significant relationship was also noted between TOP2A and the previously unexplored TUBG1 (p=0.000). Analysis of gene expression patterns according to clinicopathological variables revealed significant associations across intrinsic breast cancer subtypes.Conclusion: This study reaffirms the correlation between HER2/neu and its co-localised genes at 17q12-21, including novel candidate genes LASP1 and RPL19. We have also identified a novel relationship between TOP2A and TUBG1. Furthermore, our work represents a tentative step in the development of more accurate means of characterising HER2/neu status. As such, this work has again indicated the central role which this amplicon may play in selection of patients for treatment, not alone for Herceptin and anthracyclines, but also for taxane-based therapies, and as such, has revealed novel pathways for us to follow as we move towards our goal of individually tailored therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3137.