Ryu, Jeong-Seon; Shin, Eun-Soon; Nam, Hae-Seong; Yi, Hyeon-Gyu; Cho, Jae-Hwa; Kim, Chul-Soo; Kim, Hyun-Jung; Lee, Jong-Eun
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2011Aug ; 6 ( 8 ) :1320-9.
PMID : 21642870
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Ryu, Jeong-Seon -
Shin, Eun-Soon -
Nam, Hae-Seong -
Yi, Hyeon-Gyu -
Cho, Jae-Hwa -
Kim, Chul-Soo -
Kim, Hyun-Jung -
Lee, Jong-Eun -
ABSTRACT
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.
Adenocarcinoma/drug therapy/*genetics/mortality; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use; Bridged Compounds/administration & dosage; Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/mortality; Carcinoma, Squamous Cell/drug therapy/*genetics/mortality; Cisplatin/administration & dosage; Cohort Studies; DNA, Neoplasm/genetics; Deoxycytidine/administration & dosage/analogs & derivatives; Female; Follow-Up Studies; Humans; Lung Neoplasms/drug therapy/*genetics/mortality; Male; Middle Aged; Neoplasm Staging; Nucleoside-Phosphate Kinase/*genetics; Polymerase Chain Reaction; Polymorphism, Single Nucleotide/*genetics; Retrospective Studies; Survival Rate; Taxoids/administration & dosage; Treatment Outcome; Tumor Suppressor Proteins/*genetics
MESH
Adenocarcinoma/drug therapy/*genetics/mortality, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Bridged Compounds/administration & dosage, Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/mortality, Carcinoma, Squamous Cell/drug therapy/*genetics/mortality, Cisplatin/administration & dosage, Cohort Studies, DNA, Neoplasm/genetics, Deoxycytidine/administration & dosage/analogs & derivatives, Female, Follow-Up Studies, Humans, Lung Neoplasms/drug therapy/*genetics/mortality, Male, Middle Aged, Neoplasm Staging, Nucleoside-Phosphate Kinase/*genetics, Polymerase Chain Reaction, Polymorphism, Single Nucleotide/*genetics, Retrospective Studies, Survival Rate, Taxoids/administration & dosage, Treatment Outcome, Tumor Suppressor Proteins/*genetics
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