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High Expression of Lymphocyte-Associated Genes in Node-Negative HER2+ Breast Cancers Correlates with Lower Recurrence Rates

¹ The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; ² The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey; ³ Molecular Biology, Cellular Biology and Biochemistry Program, ⁴ Department of Biomedical Engineering, Boston University, Boston, Massachusetts; ⁵ Yale Cancer Center and ⁶ Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; ⁷ Robert Wood Johnson University Hospital, and ⁸ Cancer Institute of New Jersey, New Brunswick, New Jersey; and ⁹ BioMaPS Institute and Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey

Requests for reprints: Gyan Bhanot, BioMaPs Institute, Rutgers University, 271 Hill Center, Piscataway, NJ 08854. Phone: 732-235-9545; E-mail: gyanbhanot{at}gmail.com and Shridar Ganesan, Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-5211; E-mail: ganesash{at}umdnj.edu.

Gene expression analysis has identified biologically relevant subclasses of breast cancer. However, most classification schemes do not robustly cluster all HER2+ breast cancers, in part due to limitations and bias of clustering techniques used. In this article, we propose an alternative approach that first separates the HER2+ tumors using a gene amplification signal for Her2/neu amplicon genes and then applies consensus ensemble clustering separately to the HER2+ and HER2– clusters to look for further substructure. We applied this procedure to a microarray data set of 286 early-stage breast cancers treated only with surgery and radiation and identified two basal and four luminal subtypes in the HER2– tumors, as well as two novel and robust HER2+ subtypes. HER2+ subtypes had median distant metastasis-free survival of 99 months [95% confidence interval (95% CI), 83–118 months] and 33 months (95% CI, 11–54 months), respectively, and recurrence rates of 11% and 58%, respectively. The low recurrence subtype had a strong relative overexpression of lymphocyte-associated genes and was also associated with a prominent lymphocytic infiltration on histologic analysis. These data suggest that early-stage HER2+ cancers associated with lymphocytic infiltration are a biologically distinct subtype with an improved natural history. [Cancer Res 2007;67(22):10669–76]

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