Buccal mucosa cells as in vivo model to evaluate gefitinib activity in patients with advanced non small cell lung cancer.
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.
Loprevite
Maura
M
Medical Oncology A, National Institute for Cancer Research, S. Martino Hospital, Genoa, Italy.
Tiseo
Marcello
M
Chiaramondia
Maurizio
M
Capelletti
Marzia
M
Bozzetti
Cecilia
C
Bortesi
Beatrice
B
Naldi
Nadia
N
Nizzoli
Rita
R
Dadati
Patrizia
P
Kunkl
Annalisa
A
Zennaro
Daniela
D
Lagrasta
Costanza
C
Campanini
Nicoletta
N
Spiritelli
Elena
E
Camisa
Roberta
R
Grossi
Francesco
F
Rindi
Guido
G
Franciosi
Vittorio
V
Ardizzoni
Andrea
A
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
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D000077156:Gefitinib