Pharmacogenetic analysis of advanced non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin chemotherapy

Abstract

BACKGROUND: Genetic polymorphisms contribute toward interindividual variations in drug response. We investigated the effects of genetic polymorphisms on the clinical outcome of advanced non-small-cell lung cancer patients with first-line paclitaxel and carboplatin. MATERIALS AND METHODS: A total of 194 non-small-cell lung cancer patients were prospectively enrolled from January 2010 to January 2013. We genotyped 11 polymorphisms in seven genes involved in the glycolysis pathway and the related pharmacokinetic/pharmacodynamic pathway. Genetic associations with PET-SUV, survival outcome, and toxicity were analyzed, and in-vitro drug transport activity was measured in the oocyte system. RESULTS: Patients with the c.334 T>G and c.699 G>A homozygous variant in SLCO1B3 showed a higher incidence of grade 3/4 anemia (P=0.002). Transport activities of oocyte that overexpress the SLCO1B3 c.699 G>A variant showed a significantly decreased uptake of paclitaxel compared with the wild-type expressing oocytes. In addition, patients with GG/GA/AA genotypes of ABCB1, c.2677 T>G/A locus showed inferior progression-free survival (hazard ratio=1.49, P=0.017) compared with other genotypes. The GA genotype of HIF1A, c.1834 G>A locus was associated with inferior progression-free survival compared with the GG genotype (hazard ratio=2.47, P=0.008). CONCLUSION: This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin.