title: Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling.
abstract: OBJECTIVE
  Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age.
  
  
  METHODS
  Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER(-)/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model.
  
  
  RESULTS
  A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER(-)/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER(+)/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334).
  
  
  CONCLUSIONS
  Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.
authors.affiliation: Breast Cancer Translational Research Laboratory (BCTL) J.C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Singhal
authors.forename: Carmen
authors.initials: C
authors.lastname: Criscitiello
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen