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

Abstract

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.

On the pharmacogenetics of non-small cell lung cancer treatment

“…Previous studies reported a 2.6-fold higher TS expression with 3 copies (TSER*3) of the R than with 2 copies (TSER*2) [42]. The variable number of repeats was associated with outcome after pemetrexed treatment in patients with different malignancies, including lung cancers [43,44]. However, these data were not always confirmed in other studies in NSCLC [45][46][47].…”

“…In contrast, pharmacogenetic analyses in a randomized phase II trial aiming to optimize the administration schedule of pemetrexed and gemcitabine in 54 chemotherapy-naive patients with advanced NSCLC did not show any correlations with outcome for GGH IVS7(1478) and IVS2(1307) [49]. However, the latter trial supported the association of RFC-exon6-SNP with outcome following pemetrexed treatment [49], which was also reported in the recent research by Li and collaborators [44].…”

“…Since methylenetetrahydrofolate reductase is an important regulator of the folate homeostasis, the polymorphic variant was suggested to favor an increased inhibition of TS by pemetrexed. However, this result was not observed in 45 adenocarcinoma patients treated with pemetrexed [44].…”

“…Pemetrexed activity might indeed be affected by other mechanisms of antifolate resistance such as loss of RFC or proton-coupled folate transporter, causing impaired uptake: increased drug efflux due to overexpression of ATP-driven multidrug resistance proteins, decreased folypolyglutamate syntethase expression and/or inactivating mutations or alternative splicing defecting antifolate polyglutamylation, and increased expression of γ-glutamyl hydrolase (GGH) [30,44]. However, none of these factors has yet been validated in NSCLC [15].…”

Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations

“…7,8 Furthermore, a number of polymorphic SLC19A1 variants have been shown to influence pemetrexed tolerability and survival after therapy (Table 1). [9][10][11] More recently, the proton-coupled folate transporter has been shown to possess high affinity for pemetrexed and has been confirmed as an important mechanism of cellular influx. 12,13 A third route of cellular uptake of uncertain significance, is mediated by folate receptors (FR) -a and -b, which are anchored to the cellular membrane, transporting folate derivatives via a complex endocytotic mechanism.…”