title: Buccal mucosa cells as in vivo model to evaluate gefitinib activity in patients with advanced non small cell lung cancer.
abstract: OBJECTIVE
  To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non-small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed.
  
  
  METHODS
  Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response.
  
  
  RESULTS
  Fifty-eight patients with pretreated advanced non-small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P < 0.001).
  
  
  CONCLUSIONS
  Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.
authors.affiliation: Medical Oncology A, National Institute for Cancer Research, S. Martino Hospital, Genoa, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Loprevite
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiaramondia
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bozzetti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bortesi
authors.forename: Nadia
authors.initials: N
authors.lastname: Naldi
authors.forename: Rita
authors.initials: R
authors.lastname: Nizzoli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dadati
authors.forename: Annalisa
authors.initials: A
authors.lastname: Kunkl
authors.forename: Daniela
authors.initials: D
authors.lastname: Zennaro
authors.forename: Costanza
authors.initials: C
authors.lastname: Lagrasta
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Campanini
authors.forename: Elena
authors.initials: E
authors.lastname: Spiritelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Camisa
authors.forename: Francesco
authors.initials: F
authors.lastname: Grossi
authors.forename: Guido
authors.initials: G
authors.lastname: Rindi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Franciosi
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation / Q000379:methods*; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System; D009061:Mouth Mucosa / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D000077156:Gefitinib