title: Measurement of Domain-Specific HER2 (ERBB2) Expression May Classify Benefit From Trastuzumab in Breast Cancer.
abstract: BACKGROUND
  Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy.
  
  
  METHODS
  We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided.
  
  
  RESULTS
  HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD.
  
  
  CONCLUSIONS
  Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression.
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Carvajal-Hausdorf
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Amanda
authors.initials: A
authors.lastname: Psyrri
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: : Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. david.rimm@yale.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005110:Extracellular Space / Q000737:chemistry*; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human