Abstract Most ER+ breast cancers are treated with anti-estrogens like Tamoxifen which disrupt the Estrogen growth pathway. However, not all ER+ cases respond to this therapy. This study aims to identify genetic markers associated with increased sensitivity or resistance to Tamoxifen using outlier analysis. We collected 268 ER+ samples of gene expression data from three separate published studies on Tamoxifen treated patients with follow-up information on distant metastasis-free survival time. Genes were associated with Kaplan-Meyer survival curves based on their outlier profile and filtered, using the long-rank test, for differential survival distributions at p-value<0.05. Additional correlation analysis and PCA clustering were used to identify pathways and chromosomal regions enriched with gene markers correlated with Tamoxifen response. We find significantly over-expressed cell cycle genes correlated with poor survival together with an enrichment of chromosomal regions 17q21.33–q25.1, 17q12, 8p11.2 and 8q24.3. These amplicons were previously documented in breast cancer and contain known oncogenes ERBB2, LSM1, WHSC1L1 and HSF1 associated with more aggressive forms of the disease. Since the majority of samples enriched in the cell cycle pathway also have at least one of the amplicons, this suggests the amplifications on chromosomes 8 and 17 are associated with increased proliferation. In addition to this, a relative Oncotype DX™ score was calculated for samples using normalized expression levels and published weights. This analysis showed that high Oncotype DX™ scores are generated by tumors having either the HER2 amplicon (highest Oncotype DX™ scores), or one of the other amplicons on chromosomes 17 and 8. In contrast, low Oncotype DX™ scores were found only for tumors that do not exhibit any of the identified chromosomal aberrations. This implies that amplicons 17q21.33–q25.1, 8p11.2 and 8q24.3 may be responsible for higher proliferation and poor outcome in the setting of Tamoxifen treatment clinically observed in a subset of ER+, HER2− breast cancers. These results have significant implications for the development of targeted treatments for Tamoxifen-resistent ER+ breast cancers as well as in improving current methods of drug response prediction. Citation Information: Cancer Res 2009;69(23 Suppl):C34.