Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed-carboplatin

Purpose: To correlate candidate polymorphisms affecting pemetrexed and carboplatin activity with clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated in second-line with pemetrexed or pemetrexed plus carboplatin. Methods: Functional polymorphisms in thymidylate synthase (TS), reduced folate carrier (RFC), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and xeroderma pigmentosum group D (XPD) genes were evaluated in 208 patients either treated within randomized phase II trials NVALT-7 and GOIRC-02.2006, comparing second-line pemetrexed with pemetrexed plus carboplatin, or with the same regimens outside of these trials. Univariate and multivariate analyses correlated genotyping data with response, clinical benefit, toxicity, progression-free (PFS) and overall survival (OS) using Pearson-χ² test, log-rank test and Cox proportional hazards model. Results: Patients harboring the MTHFR-T667T variant had significantly longer PFS (5.4 versus 3.4 months; p= 0.012) and OS (16.4 versus 8.5 months; p= 0.026) than patients with CC-CT genotypes. No correlation was observed for other polymorphisms, except for XPD-Gln751Gln, which was associated with shorter PFS (p= 0.021) and OS (p= 0.044) in the subgroup of patients treated with pemetrexed plus carboplatin. Multivariate analysis confirmed the independent prognostic significance of MTHFR-C677T both in risk of disease progression (CC-CT genotypes hazard ratio [HR] 1.94, 95%CI 1.15-3.28; p= 0.012) and of death (HR 2.00, 95%CI 1.12-3.54; p= 0.018). Conclusions: MTHFR-C667T polymorphisms appear to predict survival differences in pemetrexed-treated NSCLC. These results should be validated in larger and adequately designed prospective studies using pemetrexed.