title: Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer.
abstract: BACKGROUND
  Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti-HER-2 treatment. However, commonly defined "HER-2(-)" tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm.
  
  
  METHODS
  We studied 1,150 women (median age, 58 years; range, 22-94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis.
  
  
  RESULTS
  Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2(-) by FISH, and HER-2(+) (3+ or HER-2(+) by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2(-) by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2(+) status, a HER-2 2+/HER-2(-) status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649.
  
  
  CONCLUSIONS
  A HER-2 2+/HER-2(-) status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2(+) tumors, patients with a HER-2 2+/HER-2(-) status are ideal candidates for studies testing this hypothesis.
authors.affiliation: Division of Medical Oncology, Fondazione del Piemonte per l’Oncologia/Institute for Cancer Research and Treatment, Candiolo, Italy. filippo.montemurro@ircc.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Rossi
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Furio
authors.initials: F
authors.lastname: Maggiorotto
authors.forename: Paola
authors.initials: P
authors.lastname: Berchialla
authors.forename: Franziska
authors.initials: F
authors.lastname: Kubatzki
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Tomasi
authors.forename: Stefania
authors.initials: S
authors.lastname: Redana
authors.forename: Rossella
authors.initials: R
authors.lastname: Martinello
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ponzone
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human