PURPOSE:Epidermal growth factor receptor (EGFR) is highly expressed in some gastric cancers and is implicated in cancer cell growth and proliferation. The objective of this study was to assess the in situ biologic activity of the EGFR tyrosine kinase inhibitor gefitinib in gastric tumor samples in a phase II study. METHODS:Patients with previously treated stage IV adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive gefitinib (250 or 500 mg/d). Tumor biopsies, obtained at screening and on day 28 of treatment, were assessed for biomarker expression using immunohistochemistry and analysis of apoptosis. RESULTS:One hundred sixteen tumor samples from 70 patients were available, 70 were baseline and 46 were on-therapy biopsies. At baseline, levels of EGFR expression significantly correlated with levels of phosphorylated EGFR (pEGFR; P < .001) and Ki67 expression (P = .011), but not with phosphorylated mitogen-activated protein kinase (pMAPK). After gefitinib treatment, levels of pEGFR in tumor cells were significantly reduced (P = .001); this was not the case for pMAPK and phosphorylated Akt (pAkt). However, in some cases gefitinib inhibited pAkt and these tumors had enhanced apoptosis. Likewise, there was a significant correlation between increased exposure to geftinib and enhanced apoptosis. CONCLUSION:Gefitinib reached the tumors at concentrations sufficient to inhibit EGFR activation in advanced gastric carcinoma patients, although this did not translate into clinical benefit. Overall, intratumoral phosphorylation of MAPK and Akt was not significantly inhibited by gefitinib. However, the finding that decreases in pAkt correlated with enhanced apoptosis deserves further exploration.
RCT Entities:
PURPOSE:Epidermal growth factor receptor (EGFR) is highly expressed in some gastric cancers and is implicated in cancer cell growth and proliferation. The objective of this study was to assess the in situ biologic activity of the EGFR tyrosine kinase inhibitor gefitinib in gastric tumor samples in a phase II study. METHODS:Patients with previously treated stage IV adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive gefitinib (250 or 500 mg/d). Tumor biopsies, obtained at screening and on day 28 of treatment, were assessed for biomarker expression using immunohistochemistry and analysis of apoptosis. RESULTS: One hundred sixteen tumor samples from 70 patients were available, 70 were baseline and 46 were on-therapy biopsies. At baseline, levels of EGFR expression significantly correlated with levels of phosphorylated EGFR (pEGFR; P < .001) and Ki67 expression (P = .011), but not with phosphorylated mitogen-activated protein kinase (pMAPK). After gefitinib treatment, levels of pEGFR in tumor cells were significantly reduced (P = .001); this was not the case for pMAPK and phosphorylated Akt (pAkt). However, in some cases gefitinib inhibited pAkt and these tumors had enhanced apoptosis. Likewise, there was a significant correlation between increased exposure to geftinib and enhanced apoptosis. CONCLUSION:Gefitinib reached the tumors at concentrations sufficient to inhibit EGFR activation in advanced gastric carcinomapatients, although this did not translate into clinical benefit. Overall, intratumoral phosphorylation of MAPK and Akt was not significantly inhibited by gefitinib. However, the finding that decreases in pAkt correlated with enhanced apoptosis deserves further exploration.
Authors: Carlos L Arteaga; Anne O'Neill; Stacy L Moulder; Michael Pins; Joseph A Sparano; George W Sledge; Nancy E Davidson Journal: Clin Cancer Res Date: 2008-10-01 Impact factor: 12.531
Authors: Zhang Chun-Zhi; Han Lei; Zhang An-Ling; Fu Yan-Chao; Yue Xiao; Wang Guang-Xiu; Jia Zhi-Fan; Pu Pei-Yu; Zhang Qing-Yu; Kang Chun-Sheng Journal: BMC Cancer Date: 2010-07-12 Impact factor: 4.430
Authors: T Murayama; M Inokuchi; Y Takagi; H Yamada; K Kojima; J Kumagai; T Kawano; K Sugihara Journal: Br J Cancer Date: 2009-02-17 Impact factor: 7.640