title: HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.
abstract: OBJECTIVE
  Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease.
  
  
  METHODS
  Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery.
  
  
  RESULTS
  The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors.
  
  
  CONCLUSIONS
  Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio 78284-7884.
authors.forename: D C
authors.initials: DC
authors.lastname: Allred
authors.forename: G M
authors.initials: GM
authors.lastname: Clark
authors.forename: A K
authors.initials: AK
authors.lastname: Tandon
authors.forename: R
authors.initials: R
authors.lastname: Molina
authors.forename: D C
authors.initials: DC
authors.lastname: Tormey
authors.forename: C K
authors.initials: CK
authors.lastname: Osborne
authors.forename: K W
authors.initials: KW
authors.lastname: Gilchrist
authors.forename: E G
authors.initials: EG
authors.lastname: Mansour
authors.forename: M
authors.initials: M
authors.lastname: Abeloff
authors.forename: L
authors.initials: L
authors.lastname: Eudey
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011519:Proto-Oncogenes; D016019:Survival Analysis