Differential effect of polymorphisms of CMPK1 and RRM1 on survival in advanced non-small cell lung cancer patients treated with gemcitabine or taxane/cisplatinum.

INTRODUCTION:To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum. METHODS:We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1. RESULTS:The wild-type genotypes of CMPK1 IVS1+1057 and IVS1-928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox pBonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 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/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox pBonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum. CONCLUSIONS: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/cisplatinum as the first-line regimen.

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