title: A window of opportunity study of potential tumor and soluble biomarkers of response to preoperative erlotinib in early stage non-small cell lung cancer.
abstract: BACKGROUND
  Erlotinib is highly active in EGFR mutant NSCLC, but may benefit some with wild-type tumors. We examined pre-operative erlotinib in early stage NSCLC to assess response and correlation with potential biomarkers.
  
  
  RESULTS
  Twenty-five patients were enrolled; 22 received erlotinib treatment and were evaluable (median follow-up 4.4 years). Histology was predominantly adenocarcinoma although 31% had squamous carcinoma. PET response was observed in 2 patients (9%), both with squamous carcinoma. Most (20/22) had stable disease (RECIST), with frequent minor radiographic regression and histologic findings of fibrosis/necrosis including in squamous histology. Only two had EGFR mutations identified, one with minor radiographic response and the other stable disease after 4 weeks of EGFR TKI. High pre-treatment serum levels of TGF-α correlated with primary resistance to erlotinib (p = 0.02), whereas high post-treatment soluble EGFR levels correlated with response (p = 0.03). EGFR, PTEN, cMET and AXL expression did not correlate with tumor response.
  
  
  METHODS
  Clinical stage IA-IIB NSCLC patients received erlotinib 150 mg daily for 4 weeks followed by resection. Tumor response was assessed using CT, PET and pathological response. Tumor genotype was established using Sequenom Mass ARRAY; EGFR, PTEN, cMET and AXL expression was assessed by immunohistochemistry, circulating markers of EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) by ELISA and EGFR, MET copy number by FISH.
  
  
  CONCLUSIONS
  Erlotinib appears to demonstrate activity in EGFR wild-type tumors including squamous carcinoma. Further research is needed to characterize those wild-type patients that may benefit from EGFR TKI and predictive biomarkers including TGF-α, EGFR copy and others.
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Division of Hematology and Oncology, Columbia University/New York-Presbyterian Hospital, New York, New York, USA.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Sacher
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Le
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Humberto
authors.initials: H
authors.lastname: Lara-Guerra
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakashita
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Salvarrey
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Gail
authors.initials: G
authors.lastname: Darling
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yasufuku
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Ming Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D017024:Chemotherapy, Adjuvant / Q000379:methods; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069347:Erlotinib Hydrochloride
keywords: NSCLC; erlotinib; preoperative window study