title: Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.
abstract: OBJECTIVE
  To define the biology driving the aggressive nature of breast cancer arising in young women.
  
  
  METHODS
  Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <or=45 years; older >or=65 years), 411 eligible patients (n = 200<or=45 years; n = 211>or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.
  
  
  RESULTS
  In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.
  
  
  CONCLUSIONS
  Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Carey K
authors.initials: CK
authors.lastname: Anders
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Acharya
authors.forename: David S
authors.initials: DS
authors.lastname: Hsu
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Katherine
authors.initials: K
authors.lastname: Garman
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.forename: Kelly
authors.initials: K
authors.lastname: Marcom
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.forename: Anil
authors.initials: A
authors.lastname: Potti
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009857:Oncogenes