title: A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer.
abstract: OBJECTIVE
  To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen.
  
  
  METHODS
  Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures.
  
  
  RESULTS
  Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior.
  
  
  CONCLUSIONS
  The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points.
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. torsten@interchange.ubc.ca
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.forename: David
authors.initials: D
authors.lastname: Voduc
authors.forename: Mark
authors.initials: M
authors.lastname: Ebbert
authors.forename: Tammi
authors.initials: T
authors.lastname: Vickery
authors.forename: Sherri R
authors.initials: SR
authors.lastname: Davies
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Snider
authors.forename: Inge J
authors.initials: IJ
authors.lastname: Stijleman
authors.forename: Jerry
authors.initials: J
authors.lastname: Reed
authors.forename: Maggie C U
authors.initials: MC
authors.lastname: Cheang
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D002277:Carcinoma / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D003940:Diagnostic Techniques, Endocrine; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen