title: Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC).
abstract: OBJECTIVE
  Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27.
  
  
  METHODS
  Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated.
  
  
  RESULTS
  (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs.
  
  
  CONCLUSIONS
  p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.
authors.affiliation: Translational Research Unit, Jules Bordet Institute, 125, Boulevard de Waterloo, 1000 Brussels, Belgium.
authors.forename: Rosa
authors.initials: R
authors.lastname: Giuliani
authors.forename: Virginie
authors.initials: V
authors.lastname: Durbecq
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.forename: Marianne
authors.initials: M
authors.lastname: Paesmans
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Leroy
authors.forename: Marleen
authors.initials: M
authors.lastname: Borms
authors.forename: Anita
authors.initials: A
authors.lastname: Vindevoghel
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.forename: Veronique
authors.initials: V
authors.lastname: D'Hondt
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Canon
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Veronique
authors.initials: V
authors.lastname: Cocquyt
authors.forename: Françoise
authors.initials: F
authors.lastname: Majois
authors.forename: Michel
authors.initials: M
authors.lastname: Reginster
authors.forename: Jan
authors.initials: J
authors.lastname: Demol
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kains
authors.forename: Paul
authors.initials: P
authors.lastname: Delree
authors.forename: Carine
authors.initials: C
authors.lastname: Keppens
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab