Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed.

Estefanía Arévalo,Ana Patiño-García,Patricia Martín,Josefa Salgado,Inés López,Eduardo Castañón,María Rodríguez-Ruiz,Christian Rolfo,Leire Zubiri,Marta Santisteban,Víctor Collado,Ignacio Gil-Bazo

doi:10.1186/1479-5876-12-98

Abstract

BackgroundWe studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed.MethodsTwenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3′ untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity.ResultsThe genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed.ConclusionIn our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.

Highlights

We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed
Pemetrexed, is a multitargeted antifolate drug and one of the latest active drugs against NSCLC [4] approved for the first-line [5] [6] and secondline treatment of patients with nonsquamous histology [7]
Correlation between overall response rate (ORR) to the treatment and polymorphisms We studied the potential correlation between the different polymorphisms observed and the response to the treatment obtained (Table 2)

Summary

Introduction

We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. More than 225,000 new cases were diagnosed during 2012 only in the United States of America, accounting for approximately 160,000 annual deaths [1,2]. More than 50% of the patients diagnosed with non-small cell lung cancer (NSCLC) present advanced disease (stage III and IV) at onset. The most common histology is adenocarcinoma representing approximately 80% of all cases [3]. Pemetrexed, is a multitargeted antifolate drug and one of the latest active drugs against NSCLC [4] approved for the first-line [5] (in combination with cisplatin) [6] and secondline treatment (monotherapy) of patients with nonsquamous histology [7]. Pemetrexed gained approval for its use as a single-agent maintenance therapy [8] after response/stabilization to four cycles of a platinum doublet with or without pemetrexed

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