title: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer.
abstract: BACKGROUND
  Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis.
  
  
  METHODS
  In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided.
  
  
  RESULTS
  Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P=.02), lack of estrogen receptors (P=.008), and the number of positive lymph nodes (P=.0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors--DFS: relative risk of failure (RR)=0.60 (95% confidence interval [CI]=0.44-0.83), P=.001; survival: RR=0.66 (95% CI=0.47-0.92), P =.01; RFS: RR=0.58 (95% CI=0.42-0.82), P=.002; DDFS: RR=0.61 (95% CI=0.44-0.85), P=.003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR=0.96 (95% CI=0.75-1.23), P=.74; survival: RR =0.90 (95% CI=0.69-1.19), P=.47; RFS: RR=0.88 (95% CI=0.67-1.16), P=.37; DDFS: RR=1.03 (95% CI=0.79-1.35), P=.84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P=.02) and DDFS (P=.02) but not for survival (P= .15) or RFS (P=.06).
  
  
  CONCLUSIONS
  These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project, Department of Human Oncology, Allegheny University of Health Sciences, Pittsburgh, PA 15212-5234, USA. spaik@pgh.auhs.edu
authors.forename: S
authors.initials: S
authors.lastname: Paik
authors.forename: J
authors.initials: J
authors.lastname: Bryant
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.forename: B
authors.initials: B
authors.lastname: Fisher
authors.forename: E
authors.initials: E
authors.lastname: Tan-Chiu
authors.forename: D
authors.initials: D
authors.lastname: Hyams
authors.forename: E R
authors.initials: ER
authors.lastname: Fisher
authors.forename: M E
authors.initials: ME
authors.lastname: Lippman
authors.forename: D L
authors.initials: DL
authors.lastname: Wickerham
authors.forename: N
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry* / Q000188:drug therapy*; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012189:Retrospective Studies; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases