title: Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study.
abstract: BACKGROUND
  Relationships between clinical outcomes and epidermal growth factor receptor (EGFR)-related tumor markers were investigated in patients with advanced non-small cell lung cancer.
  
  
  METHODS
  Patients with stage IIIB/IV non-small cell lung cancer (0-2 prior regimens) received erlotinib (150 mg PO per day). Response and survival were evaluated, and tumor samples were assessed by immunohistochemistry (EGFR, phosphorylated mitogen-activated protein kinase, and phosphorylated AKT protein expression), fluorescence in situ hybridization (FISH; EGFR gene copy number), and DNA sequencing (EGFR, KRAS gene mutations).
  
  
  RESULTS
  Among 311 patients, 8% had a complete/partial response; the disease control rate was 66%. Median Overall survival (OS) was 6.1 months; 1-year survival rate was 27.2%. Two of 4 patients with EGFR mutations had tumor responses, versus 2/68 with wild-type EGFR (p = 0.014). Progression-free survival (PFS) (HR = 0.31) and OS (HR = 0.33) were significantly prolonged in patients with EGFR mutations. Response rate was significantly higher in patients with EGFR FISH-positive (17%) than FISH-negative tumors (6%), and both PFS (HR = 0.58) and OS (HR = 0.63) significantly favored patients with EGFR FISH-positive tumors; median OS was 8.6 months in the EGFR FISH-positive group. None of 17 patients with a KRAS mutation had a tumor response, but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance. Neither phosphorylated mitogen-activated protein kinase nor phosphorylated AKT immunohistochemistry status had a significant effect on PFS and OS with erlotinib.
  
  
  CONCLUSIONS
  The presence of EGFR mutations and EGFR FISH-positive tumors may predispose patients to achieving better outcomes on erlotinib, but may have a beneficial impact on prognosis (irrespective of treatment). Prospective, placebo-controlled studies are needed to determine the predictive value of the putative biomarkers.
authors.affiliation: Department of Oncological Pneumology, Central Clinic Bad Berka, Bad Berka, Germany. cp.schneider.pne@zentralklinikbad-berka.de
authors.forename: Claus-Peter
authors.initials: CP
authors.lastname: Schneider
authors.forename: David
authors.initials: D
authors.lastname: Heigener
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schott-von-Römer
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gütz
authors.forename: Eckart
authors.initials: E
authors.lastname: Laack
authors.forename: Werner
authors.initials: W
authors.lastname: Digel
authors.forename: Wolf-Rüdiger
authors.initials: WR
authors.lastname: Guschall
authors.forename: Andreas
authors.initials: A
authors.lastname: Franke
authors.forename: Heinrich
authors.initials: H
authors.lastname: Bodenstein
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidtgen
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D018628:Gene Dosage; D005858:Germany; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins