title: Clinical significance of pretreatment serum amphiregulin and transforming growth factor-alpha, and an epidermal growth factor receptor somatic mutation in patients with advanced non-squamous, non-small cell lung cancer.
abstract: Circulating amphiregulin and transforming growth factor-alpha (TGF-alpha) have been found to be correlated with an unfavorable response to gefitinib based on the identification of patients with a higher probability of resistance to the drug. However, the association between an epidermal growth factor receptor (EGFR) somatic mutation and the overexpression of its ligands has not been determined. To verify the clinical significance of the two serum markers and EGFR mutation status, we determined serum amphiregulin and TGF-alpha levels by enzyme-linked immunosorbent assay in 93 patients with advanced non-squamous, non-small cell lung cancer and EGFR somatic mutation status using the peptic nucleic acid-locked nucleic acid clamp method in 46 cases. The relationship between each independent clinicopathological variable and the response to gefitinib therapy was examined. We also evaluated the risk factors associated with prognosis. Fourteen (41.0%) of 34 progressive disease cases were positive for amphiregulin (P = 0.007). Eleven (32.4%) of 34 progressive disease cases were positive for TGF-alpha (P = 0.005). The median survival time of patients with the EGFR somatic mutation was significantly longer (P = 0.01). The same was true of amphiregulin- (P = 0.046) and TGF-alpha-negative patients (P < 0.01). In multivariate analysis, serum TGF-alpha positivity (hazard ratio, 2.558; P = 0.005) and the wild type EGFR gene (hazard ratio, 1.894; P = 0.003) were significant independent prognostic factors. Our study demonstrates that the status of the serum EGFR ligand, in addition to EGFR activating mutation, is a predictive factor for response to gefitinib therapy.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. masago@kuhp.kyoto-u.ac.jp
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Masago
authors.forename: Shiro
authors.initials: S
authors.lastname: Fujita
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Hatachi
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukuhara
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Sakuma
authors.forename: Masataka
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Yung Haku
authors.initials: YH
authors.lastname: Kim
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mio
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
mesh_terms: D066258:Amphiregulin; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D016019:Survival Analysis; D016211:Transforming Growth Factor alpha / Q000097:blood*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors