title: High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates.
abstract: 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.
authors.affiliation: The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.forename: Gul S
authors.initials: GS
authors.lastname: Dalgin
authors.forename: Daniel
authors.initials: D
authors.lastname: Scanfeld
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Charles
authors.initials: C
authors.lastname: DeLisi
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Harris
authors.forename: Nicola
authors.initials: N
authors.lastname: Barnard
authors.forename: Maritza
authors.initials: M
authors.lastname: Martel
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D005810:Multigene Family; D009361:Neoplasm Invasiveness; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D012008:Recurrence
chemical_list: D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases