Effect of wnt aberrant methylation and epidermal growth factor receptor pathway mutation on responsiveness of non-small cell lung cancer to gefitinib and erlotinib.

Abstract

e18011 Background: Wnt or Epidermal growth factor receptor (EGFR) signaling pathways play critical roles in predicting outcome of non-small-cell lung cancer treatment. Little is known about the synchronous effect on EGFR tyrosine-kinase inhibitors (EGFR-TKIs) treatment in NSCLC. Methods: Tumor samples from 138 patients with stages IIIB to IV NSCLC taking EGFR-TKIs therapy were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography. Wnt antagonist methylation,including sFRP1, sFRP2, sFRP5, DKK-3, WIF-1, APC, were also analyzed from these samples through methylation specific PCR method. Results: We found that EGFR mutations were related to smoking status and gender, while methylation of wnt antagonists did not have these trends. The wnt antagonists tend to methylate simultaneously. Methylation of sFRP1 and sFRP5 are reversely correlated with EGFR mutation (P=0.037 and P=0.048). Patients with EGFR mutations have a significant longer progression-free survival (PFS) than those without mutations (7.8 ms vs 2.0 ms, P=0.009), while patients with methylation of sFRP5 and WIF-1 have a significant shorter PFS than those without methylation in TKI treatment (1.2 ms Vs 5.3 ms, P=0.002; 1.1 ms Vs 4.9 ms, P=0.006). Methylation of sFRP5 is an independent factor affecting PFS in multivariate analysis. Patients with sFRP1 methylation have no a significant shorter PFS than patients without its methylation in TKI therapy. Patients with WIF-1 methylation have a significant shorter overall survival (OS) than patients without its methylation (P=0.006 by log-rank test). Conclusions: Patients without sFRP5 or WIF-1 methylation are more likely to benefit from EGFR tyrosine-kinase inhibitor (TKIs) therapy. Methylation of sFRP5 and WIF-1 could be predictive markers related to poor PFS in TKIs treatment.