Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefitinib responsiveness in non-small-cell lung cancer

OBJECTIVE: Limited availability of tumoral tissue in non-small-cell lung cancer and presence of epidermal growth factor receptor mutation-independent responses call for investigation of other molecular predictive marker of gefitinib responsiveness. Therefore, CA repeat polymorphism in intron 1 was analyzed for its association with gefitinib responsiveness together with epidermal growth factor receptor mutation in Korean patients. PATIENTS AND METHODS: For 86 advanced non-small-cell lung cancer patients treated with gefitinib, epidermal growth factor receptor mutation was analyzed by direct sequencing (exons 18-21) from tumor tissue and CA repeat polymorphism was assessed by fragment length analysis from tumor and/or normal tissue. RESULTS: CA repeat status was identical in 33 patients with matched tumor and normal tissue. CA repeat was low (sum of both alleles ≤37) in 40 (46.5%) and high (sum ≥38) in 46 (53.5%) patients. Although epidermal growth factor receptor mutation was more frequent in high CA repeat patients [17.5% (7/40) in low vs. 28.3% (13/46) in high, P=0.18], response rate was higher in low CA repeat patients [25.0% (10/40) in low vs. 13.0% (6/46) in high, P=0.16]. In multivariate analysis, low CA repeat was associated with better objective response (odds ratio 7.1, 95% confidence interval 1.2-40.8; P=0.029) and time-to-progression (hazard ratio 0.54, 95% confidence interval 0.34-0.88; P=0.014), independent of the epidermal growth factor receptor mutational status. CA repeat status was not associated with epidermal growth factor receptor expression. CONCLUSION: Low number of CA repeats in intron 1 of epidermal growth factor receptor is associated with gefitinib responsiveness in non-small-cell lung cancer patients independent of epidermal growth factor receptor mutation.