Single nucleotide polymorphisms in FAS and FASL and sensitivity to gefitinib in patients with advanced non-small cell lung cancer.

Abstract

e13529 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play a key role in the management of advanced non-small cell lung cancer (NSCLC). Numerous investigations have demonstrated an association between the presence of somatic mutations in EGFR and the sensitivity to gefitinib or erlotinib in NSCLC. Since genetic polymorphisms are more prevalent than mutations in human genome, some of them may be more practical as genetic biomarkers to predict the sensitivity to EGFR-TKIs. The FAS-FASL system plays crucial role in apoptotic signaling in many tumor cells. Here, we assessed the possibility that single nucleotide polymorphisms (SNPs) in FAS and FASL could be used to predict the sensitivity to gefitinib in patients with advanced NSCLC. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms. SNPs in the promoter region of the FAS (−1377G/A and −670A/G) and FASL (−844T/C) were assessed in 88 advanced NSCLC patients treated with gefitinib. The Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association between genotypes and sensitivity to gefitinib was validated by statistical tests. Results: For FAS -1377G/A, the clinical benefit rates (CBR) of gefitinib in advanced NSCLC patients were 31.3%, 61.1% or 74.3% (p = 0.014) in AA, GA or GG genotypes, respectively. For FAS −670A/G, the CBR were 32.0%, 78.0% or 57.9% (p = 0.001) in GG, AG or AA genotypes. For FASL - 844T/C, the CBR were 65.2%, 57.1% or 50% (p = 0.276) in CC, CT or TT genotypes. FAS -670 GG genotype carriers also had a significantly shorter survival time after the treatment of gefitinib than variation allele carriers (AG or AA genotypes), the overall survival time were 26 and 47 months (p = 0.012), respectively. Conclusions: FAS -1377G/A and -670A/G polymorphisms may be predictive for sensitivity to gefitinib in patients with advanced NSCLC. No significant financial relationships to disclose.