Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers.
A number of different clinical characteristics and molecular markers related to epidermal growth factor receptor (EGFR) activation have been reported to singly correlate with therapeutic activity of EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the predictive value on gefitinib outcomes of a comprehensive panel of molecular parameters in advanced NSCLC patients. EGFR and K-ras mutations were detected by direct sequencing on tumor DNA from paraffin embedded samples. EGFR and HER2 gene copy number was assessed by FISH. EGFR protein expression was quantified by immunohistochemistry. EGFR gene intron 1 polymorphism was assessed on genomic DNA isolated from venous whole blood samples. Ninety-one patients were prospectively enrolled and the overall gefitinib response rate was 18.7% (2 complete and 15 partial responses). Sex (p=0.005), non-smoking status (p=0.010), skin toxicity (p=0.020), EGFR gene mutations (p<0.001) and EGFR FISH positivity (p=0.016) were found to be associated with gefitinib response. K-ras mutation was detected in only seven non-responder patients. The median overall survival was of 10 months. Only non-smoking status and EGFR intron 1 polymorphism showed a statistically significant correlation with survival (p=0.031 and 0.044, respectively). In conclusion, we have confirmed the role of EGFR gene mutation as predictor of response to EGFR TKIs. Moreover, EGFR gene copy number and, potentially, also EGFR intron 1 polymorphism could aid in better prediction of EGFR TKI responsiveness in advanced NSCLC.
Tiseo
Marcello
M
Division of Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy. mtiseo@ao.pr.it
Rossi
Giulio
G
Capelletti
Marzia
M
Sartori
Giuliana
G
Spiritelli
Elena
E
Marchioni
Alessandro
A
Bozzetti
Cecilia
C
De Palma
Giuseppe
G
Lagrasta
Costanza
C
Campanini
Nicoletta
N
Camisa
Roberta
R
Boni
Luca
L
Franciosi
Vittorio
V
Rindi
Guido
G
Ardizzoni
Andrea
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D006801:Humans; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077156:Gefitinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human