Scientific publications

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

Arévalo E, Castañón E, López I, Salgado J, Collado V, Santisteban M, Rodríguez-Ruiz M, Martín P, Zubiri L, Patiño-García A, Rolfo C, Gil-Bazo I.
Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain 

Magazine: Journal of Translational Medicine

Date: Apr 14, 2014

Clinical Genetics Unit [SP] Medical Oncology

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.

Twenty-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.

The 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.

In 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.

CITATION  J Transl Med. 2014 Apr 14;12:98. doi: 10.1186/1479-5876-12-98.

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