title: Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Arévalo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Castañón
authors.forename: Inés
authors.initials: I
authors.lastname: López
authors.forename: Josefa
authors.initials: J
authors.lastname: Salgado
authors.forename: Víctor
authors.initials: V
authors.lastname: Collado
authors.forename: Marta
authors.initials: M
authors.lastname: Santisteban
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Ruiz
authors.forename: Patricia
authors.initials: P
authors.lastname: Martín
authors.forename: Leire
authors.initials: L
authors.lastname: Zubiri
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-García
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain. igbazo@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gil-Bazo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D017931:DNA Primers; D005260:Female; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics*; D044465:White People
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase
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