Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced no
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RESEARCH
Open Access
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 Arévalo1†, Eduardo Castañón1†, Inés López2, Josefa Salgado3, Víctor Collado2, Marta Santisteban1, María Rodríguez-Ruiz4, Patricia Martín1, Leire Zubiri4, Ana Patiño-García3, Christian Rolfo5 and Ignacio Gil-Bazo1,2*
Abstract Background: 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. Methods: 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. Results: 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. Conclusion: 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. Keywords: Thymidylate synthase, Polymorphisms, Epidermal growth factor receptor, Predictive factors, Prognostic factors, Non-small cell lung cancer
* Correspondence: [email protected] † Equal contributors 1 Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain 2 Division of Oncology, Center for Applied Medical Research (CIMA), 31008 Pamplona, Spain Full list of author information is available at the end of the article © 2014 Arévalo et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made availabl
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