Differential Effect of Polymorphisms of CMPK1 and RRM1 on Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with Gemcitabine or Taxane Doublets

초록

Purpose: To determine whether genetic variations in CMPK1 or RRM1, which are involving the pharmacodynamics of gemcitabine, differentially affect the outcomes of NSCLC patients treated with gemcitabine or taxane doublets. Patients and Methods: We evaluated the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane doublets (159), and 14 tagging single-nucleotide polymorphisms (tSNPs): four in CMPK1 (IVS1+1057 C>A, IVS1–928 C>A, IVS5+592 C>T, 1047 C>T) and 10 in RRM1 (–756 T>C, –269 C>A, IVS1–2374 T>C, IVS4+80 G>A, IVS7+25 A>C, IVS7–1246 C>T, IVS7–425 A>G, IVS8+287 T>C, Arg284Arg C>A, IVS9–242 T>C). Results: The wild-type genotypes of CMPK1 IVS1+1057 and IVS1–928 were associated with shorter overall survival in patients treated with the gemcitabine doublet (aHRs = 1.97 and 1.89; Cox PBonferroni = .008 and .020), whereas this effect was not observed in patients treated with taxane doublets. No associations were observed for the other two CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1–2374 TT, IVS7+25 AA, IVS7–425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine doublet (aHRs = 3.00, 2.89, 3.14, and 3.00; Cox PBonferroni = .007, .012, .006, and .007). However, these effects were not observed in patients treated with taxane doublets. Conclusion: These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine doublet as the first-line regimen.