title: Differential expression of the insulin-like growth factor receptor among early breast cancer subtypes.
abstract: BACKGROUND
  We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes.
  
  
  METHODS
  Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers.
  
  
  RESULTS
  After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035).
  
  
  CONCLUSIONS
  Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.
authors.affiliation: Department of Medical Oncology, 251 Airforce General Hospital, Athens, Greece.
authors.forename: Giannis
authors.initials: G
authors.lastname: Mountzios
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Aivazi
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kostopoulos
authors.affiliation: Department of Pathology, University Hospital of Patras, Rion, Greece.
authors.forename: Helen P
authors.initials: HP
authors.lastname: Kourea
authors.affiliation: Health Data Specialists Ltd, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kouvatseas
authors.affiliation: Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.affiliation: 1st Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Zebekakis
authors.affiliation: Department of Pathology, "Papageorgiou" Hospital, Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Efstratiou
authors.affiliation: First Department of Medicine, "Laiko" General Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Department of Pathology, "Evangelismos" Hospital, Athens, Greece.
authors.forename: Chrisanthi
authors.initials: C
authors.lastname: Vamvouka
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Chrisafi
authors.affiliation: Pathology Department National & Kapodistrian University of Athens, Athens, Greece.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stofas
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
authors.forename: Angelos
authors.initials: A
authors.lastname: Koutras
authors.affiliation: Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Galani
authors.affiliation: First Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D017451:Receptors, Somatomedin