title: EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial.
  
  
  METHODS
  Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130).
  
  
  RESULTS
  Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28-3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073).
  
  
  CONCLUSIONS
  High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.
authors.affiliation: Department of Pathology, Yale University School of Medicine, 310 Cedar Street BML116, New Haven, CT 06520, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ballman
authors.affiliation: Department of Medical Oncology, Pitie-Salpetriere Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Vassilakopoulou
authors.affiliation: Section of Biostatistics, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Dueck
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Reinholz
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: K
authors.initials: K
authors.lastname: Tenner
authors.affiliation: Department of Medical Oncology, University of Washington/Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Seattle, WA 98109, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gralow
authors.affiliation: Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 8, New York, NY 10065, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hudis
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh Cancer Institute and UPMC Cancer Center, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: 1] Department of Medical Oncology, Papageorgiou General Hospital, Aristotle University of Thessaloniki School of Medicine, Efkarpia Peripheral Road Stavroupoli, 56429 Thessaloniki, Greece [2] Hellenic Cooperative Oncology Group (HeCOG), Laskaridou 1, 11524 Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Anatomic Pathology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: McCullough
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.affiliation: 1] Hellenic Cooperative Oncology Group (HeCOG), Laskaridou 1, 11524 Athens, Greece [2] Second Department of Internal Medicine Propaedeutic, Oncology Section, Attikon University Hospital, University of Athens Medical School, 1 Rimini Street, Haidari, 12462 Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Psyrri
authors.affiliation: Department of Pathology, Yale University School of Medicine, 310 Cedar Street BML116, New Haven, CT 06520, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D015996:Survival Rate; D046888:Tissue Array Analysis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human