title: Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients.
abstract: BACKGROUND
  Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization.
  
  
  METHODS
  We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes--basal-like, ERBB2, luminal A/B and normal-like--and characterized these subtypes extensively with the use of conventional clinical variables.
  
  
  RESULTS
  We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders.
  
  
  CONCLUSIONS
  We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobel väg 12A, SE-171 77 Stockholm, Sweden. calza@med.unibs.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Calza
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: Gert
authors.initials: G
authors.lastname: Auer
authors.forename: Judith
authors.initials: J
authors.lastname: Bjöhle
authors.forename: Sigrid
authors.initials: S
authors.lastname: Klaar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kronenwett
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Lance
authors.initials: L
authors.lastname: Miller
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploner
authors.forename: Johanna
authors.initials: J
authors.lastname: Smeds
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D009154:Mutation