Genetic polymorphism in ATIC is associated with effectiveness and toxicity of pemetrexed in non-small-cell lung cancer

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.