title: Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.
abstract: OBJECTIVE
  Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes.
  
  
  METHODS
  Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance.
  
  
  RESULTS
  Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa.
  
  
  CONCLUSIONS
  Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.
authors.affiliation: University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Maggie Chon U
authors.initials: MC
authors.lastname: Cheang
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Eva
authors.initials: E
authors.lastname: Carrasco
authors.forename: Rosalía
authors.initials: R
authors.lastname: Caballero
authors.forename: Scott
authors.initials: S
authors.lastname: Tyldesley
authors.forename: Karen
authors.initials: K
authors.lastname: Gelmon
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011980:Receptors, Progesterone