Polymorphisms in thymidylate synthase and reduced folate carrier (SLC19A1) genes predict survival outcome in advanced non-small cell lung cancer patients treated with pemetrexed-based chemotherapy

The aim of this study was to evaluate the association between thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR) and reduced folate carrier (SLC19A1) gene polymorphisms and the treatment efficacy of pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Advanced NSCLC patients received pemetrexed and cisplatin every three weeks. Polymorphisms in the TS, MTHFR and SLC19A1 genes were detected in peripheral blood samples using DNA sequencing and Taqman PCR. An analysis of gene polymorphisms was performed with respect to the progression-free survival (PFS), response rate (RR) and overall survival (OS) of patients treated with pemetrexed. The median PFS times for patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes were significantly longer than those of patients with the 2R/3G, 3C/3G or 3G/3G genotypes (P=0.036). Patients with the SLC19A1 CC genotype had a significantly longer median OS compared with individuals with the homozygous and heterozygous genotypes (12.2 vs. 8.9 and 7.3 months, respectively; P=0.022). The PFS and OS did not differ for the three genotypes of MTHFR assessed. The RR was higher in patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes than in the other groups (P=0.044). The polymorphisms of the 5′-UTR of the TS gene and exon 6 (2522) C/T of the SLC19A1 gene predict the survival of advanced NSCLC patients treated with pemetrexed. However, a large scale clinical trial is required to validate these findings.