title: Presence of HER4 associates with increased sensitivity to Herceptin in patients with metastatic breast cancer.
abstract: BACKGROUND
  HER2 overexpression, or rather HER2 gene amplification, is indicative for Herceptin therapy in both metastatic and pre-metastatic breast cancer patients. Patient's individual sensitivity to Herceptin treatment, however, varies enormously and spans from effectual responsiveness over acquired insensitivity to complete resistance from the outset. Thus no predictive information can be deduced from HER2 determination so that molecular biomarkers indicative for Herceptin sensitivity or resistance need to be identified. Both ErbB receptor-dependent signalling molecules as well as HER2-related ErbB receptor tyrosine kinases, known to mutually interact and to cross-regulate each other are prime candidates to be involved in cellular susceptibility to Herceptin.
  
  
  METHODS
  Using immunohistochemistry and fluorescence in situ hybridisation, we retrospectively investigated primary breast cancer tissues from 48 patients who were under Herceptin treatment. We quantified the gene copy numbers of all HER receptors and evaluated their coexpression profile. Moreover the HER2 phosphorylation state, the ratio of native to truncated HER2, p27(kip1) and PTEN expression were objects of this study.
  
  
  RESULTS
  Above all markers investigated in this study Kaplan-Meier and Cox regression analysis revealed a significant positive impact of HER4 (co-)expression on overall survival from beginning of antibody therapy. Both HER4 expression and HER4 gene amplification emerged as independent prognostic markers in Herceptin-treated breast cancer patients and responsiveness to Herceptin turned out to be more efficient if tumour cells show HER4 expression.
  
  
  CONCLUSIONS
  Although HER4 is known to potentially exert a tumour cell killing activity and in turn to have a favourable impact in breast cancer patients we demonstrate here the first time that HER4 expression prolongs overall survival in Herceptin-treated patients. Elucidating HER4 receptor function in the context of Herceptin treatment will advance the design of highly efficient receptor targeting. By then we need to extend the analysis of breast cancer by allowing for HER2/HER4 coexpression by which valuable additional prognostic and predictive information might possibly be revealed.
authors.affiliation: Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. andrea.sassen@klinik.uni-regensburg.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Sassen
authors.forename: Simone
authors.initials: S
authors.lastname: Diermeier-Daucher
authors.forename: Manuela
authors.initials: M
authors.lastname: Sieben
authors.forename: Olaf
authors.initials: O
authors.lastname: Ortmann
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005260:Female; D018628:Gene Dosage; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D066247:Receptor, ErbB-4; D012189:Retrospective Studies; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human; C494929:PTEN protein, human