title: Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers.
abstract: Serum levels of amphiregulin and transforming growth factor-alpha (TGF-alpha), which were identified previously to be expressed at high levels in non-small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF-alpha responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF-alpha levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF-alpha was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF-alpha concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF-alpha and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF-alpha positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF-alpha in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takano
authors.forename: Masaya
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hayama
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Kouki
authors.initials: K
authors.lastname: Inai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishimura
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000077156:Gefitinib; D006023:Glycoproteins / Q000096:biosynthesis / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000097:blood*; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / 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; D000077156:Gefitinib