title: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.
abstract: OBJECTIVE
  Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined.
  
  
  METHODS
  Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: </= 45 years, n = 200; older: >/= 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed.
  
  
  RESULTS
  Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERalpha mRNA (P < .0001), ERbeta (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERbeta and higher EGFR mRNA expression were significant predictors of inferior DFS.
  
  
  CONCLUSIONS
  This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.
authors.affiliation: Duke University Medical Center, Box 3841, 3829 Duke South, Red Zone, Durham, NC 27710, USA. ander118@mc.duke.edu
authors.forename: Carey K
authors.initials: CK
authors.lastname: Anders
authors.forename: David S
authors.initials: DS
authors.lastname: Hsu
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Acharya
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: P Kelly
authors.initials: PK
authors.lastname: Marcom
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Febbo
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Anil
authors.initials: A
authors.lastname: Potti
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone