title: Plasma transforming growth factor alpha and amphiregulin protein levels in NCIC Clinical Trials Group BR.21.
abstract: OBJECTIVE
  To evaluate the prognostic and predictive significance of plasma levels of the epidermal growth factor receptor (EGFR) ligands, transforming growth factor α (TGF-α) and amphiregulin, in patients with non-small-cell lung cancer (NSCLC) enrolled in NCIC Clinical Trials Group BR.21 comparing erlotinib with placebo.
  
  
  METHODS
  TGF-α and amphiregulin were assessed retrospectively by enzyme-linked immunosorbent assay from available prospectively collected baseline plasma samples in 565 of 731 BR.21 patients. Cutoff points were determined for both amphiregulin (low, <10 pg/mL; high, ≥10 pg/mL) and TGF-α (low, ≤12 pg/mL; high, >12 pg/mL) using a graphical method. Cox regression models were used to correlate biomarker data and baseline characteristics with outcomes including overall (OS) and progression-free survival (PFS).
  
  
  RESULTS
  High TGF-α and amphiregulin were associated with poorer performance status (P=.06 and P<.0001, respectively) and no prior platinum therapy (P=.06 and P=.02, respectively). High amphiregulin was also associated with anemia (P=.001), increased lactate dehydrogenase (P=.03), ever-smokers (P=.04), and non-Asian ethnicity (P=.001). Patients on the placebo arm with high amphiregulin had poorer OS than patients with low amphiregulin (hazard ratio [HR]=1.88; 95% CI, 1.34 to 2.64; P=.0002), which remained significant in multivariate analysis. Amphiregulin levels did not predict for benefit from erlotinib (interaction P=.87). Conversely, TGF-α levels did not have prognostic significance, but high TGF-α predicted lack of benefit from erlotinib compared with low TGF-α (TGF-α low, OS HR=0.66; 95% CI, 0.54 to 0.81; P<.0001; high, OS HR=1.32; 95% CI, 0.73 to 2.39; P=.36; interaction P=.04).
  
  
  CONCLUSIONS
  High baseline amphiregulin is a poor prognostic factor, whereas high baseline TGF-α predicts for lack of benefit from erlotinib in advanced NSCLC.
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, Box 926, 3rd Floor TOHRCC, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6. caddison@ohri.ca
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhao
authors.forename: Aurélie
authors.initials: A
authors.lastname: Le Maître
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
mesh_terms: D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy; D066255:EGF Family of Proteins; D000069347:Erlotinib Hydrochloride; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use; D012189:Retrospective Studies; D016211:Transforming Growth Factor alpha / Q000097:blood*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D000069347:Erlotinib Hydrochloride