title: Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.
abstract: OBJECTIVE
  Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated according to the previously described molecular subtypes based on the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes.
  
  
  METHODS
  We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with clinical variables and several prognostic signatures on publicly available microarray studies (>2,100 patients).
  
  
  RESULTS
  Multivariate analysis showed that in the ER+/HER2- subgroup, only the proliferation module and the histologic grade were significantly associated with clinical outcome. In the ER-/HER2- subgroup, only the immune response module was associated with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance was limited to the ER+/HER2- subgroup.
  
  
  CONCLUSIONS
  Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2- subtype and the common denominator of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated with prognosis in the ER-/HER2- and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models and to identify new therapeutic strategies in the specific molecular subgroups.
authors.affiliation: Medical Oncology Department, Jules Bordet Institute.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Pratyaksha
authors.initials: P
authors.lastname: Wirapati
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bontempi
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen / Q000096:biosynthesis
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human