Thymidylate synthase (TS) polymorphisms (Pol) in buffy coat-derived genomic DNA as a clinical outcome predictor in non-Asian stage III/IV non-small cell lung cancer (NSCLC) patients (pts) receiving pemetrexed (Pem).

Abstract

e19112 Background: TS is the main biological target of the antifolate Pem. Some TS Pol may confer a short survival and a poor response to antifolate-treated colo-rectal cancer pts. Whether TS genotype has an independent prognostic/predictive impact on non-Asian advanced NSCLC pts treated with Pem is unknown. Methods: Twenty-five non-Asian advanced NSCLC pts treated with Pem-based regimens (1st, 2nd or 3rd line) were included. Genomic DNA was isolated from periferal blood prior to treatment. The variable number of tandem repeat (VNTR) Pol, the G>C single nucleotide Pol (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) Pol were analyzed and correlated with response rate (RR), progression-free survival (PFS), overall-survival (OS) and toxicity (Tx). Results: Regarding the VNTR Pol, most of the pts showed 2R/2R or 3R/2R Pol (17 pts; 68%), and 8 pts (32%) showed 3R/3R or 3R/4R Pol. A SNP (G>C) in VNTR was observed in 18 pts (72%). The Pol found in the 3´UTR region were +6/+6 in 12 pts (48%), +6/-6 in 11 pts (44%) and -6/-6 in 2 pts (8%). In the subgroup of T3-T4 pts, there was a higher RR among those showing 3R/3R Pol than those with 2R/2R Pol (100% vs 83.8%; p=0.029). The genotype +6/+6 predicted a higher RR among active/former smokers (A/FS) compared to +6/-6 (100% vs 37.5%; p=0.026). A 3R/3R Pol followed by 2R/2R and 2R/3R Pol predicted a superior RR in pts with EGFR mutations (p=0.018). Overall, a trend towards a better PFS in pts showing 2R/2R Pol was found (p=0.076). The cohort’s median overall survival (OS) was not reached during follow-up. The most frequent Tx was grade (G)1 anemia (28%) and nausea (20%) and G2 leucopenia (40%). G3-4 anemia (4%), leucopenia (16%), neutropenia (4%), astenia (8%) and dyspnea (4%) were uncommon but more frequent in pts with 2R/2R Pol (p=0.545). Conclusions: In this cohort of NSCLC pts 3R/3R Pol among T3-T4 pts and EGFR mutant pts and +6/-6 bp among A/FS significantly predicted a higher RR to Pem and may aid in treatment selection. Tx was not significantly correlated with a specific TS genotype. These interesting preliminary data warrant further validation in larger series.