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Pharmacodynamic Studies of Gefitinib in Tumor Biopsy Specimens From Patients With Advanced Gastric Carcinoma

Federico Rojo, Josep Tabernero, Joan Albanell, Eric Van Cutsem, Atsushi Ohtsu, Toshihiko Doi, Wasaburo Koizumi, Kuniaki Shirao, Hiroya Takiuchi, S. Ramon Cajal, José Baselga

From the Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain; the University Hospital Gasthuisberg, Leuven, Belgium; the National Cancer Center Hospital E, Chiba; the Kitasato University E Hospital, Kanagawa; the National Cancer Centre Hospital, Tokyo; and the Osaka Medical College, Osaka, Japan.

Address reprint requests to José Baselga, MD, Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain; e-mail: jbaselga{at}vhebron.net

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.

Supported by AstraZeneca, Macclesfield, Cheshire, United Kingdom.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31, June 3, 2003.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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