A pharmacogenetics study of platinum-based chemotherapy in lung cancer: polymorphism and its genetic interaction with are associated with response and survival.

The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter gene. We aimed to investigate the association of platinum efflux transporter gene polymorphism and combined and polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. We genotyped thirteen tagging and functional SNPs of in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined rs2233914 and rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; = 0.003). And the combined genotypes of the functional rs10759637 of and the nonsynonymous rs2231142 (Log-rank = 5.20×10; HR 1.47; 95 % CI 1.19-1.81; = 0.007) or linked rs4148157 of were significantly associated with poor survival. This study reveals divergent association of polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of and on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction.