title: Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial.
abstract: OBJECTIVE
  Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.
  
  
  METHODS
  Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.
  
  
  RESULTS
  Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2(+) tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6-2.1 for RFS and HR, 1.3; 95% CI, 0.7-2.5 for OS].
  
  
  CONCLUSIONS
  HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Maggie C U
authors.initials: MC
authors.lastname: Cheang
authors.forename: K David
authors.initials: KD
authors.lastname: Voduc
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Chia
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Sherri
authors.initials: S
authors.lastname: Davies
authors.forename: Inge J
authors.initials: IJ
authors.lastname: Stijleman
authors.forename: Carole
authors.initials: C
authors.lastname: Davis
authors.forename: Mark T W
authors.initials: MT
authors.lastname: Ebbert
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000145:classification* / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D018572:Disease-Free Survival; D015251:Epirubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D018943:Anthracyclines; D014408:Biomarkers, Tumor; D002945:Cisplatin; D003520:Cyclophosphamide; D003561:Cytarabine; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human