title: Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takiuchi
authors.forename: S
authors.initials: S
authors.lastname: Ramon y Cajal
authors.forename: S
authors.initials: S
authors.lastname: Ramon Cajal
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D000077156:Gefitinib