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Increases of Amphiregulin and Transforming Growth Factor- in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non–Small Cell Lung Cancers

¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Departments of ² Molecular and Internal Medicine and ³ Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; ⁴ Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan; and ⁵ Kanagawa Cancer Center Research Institute, Kanagawa, Japan

Requests for reprints: Yusuke Nakamura, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke{at}ims.u-tokyo.ac.jp.

Serum levels of amphiregulin and transforming growth factor- (TGF-), 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- responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF- 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- 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- concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF- and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF- positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF- in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC.

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