Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer.
BACKGROUND
It has not been well established whether genetic variations can be biomarkers for clinical outcome of gemcitabine therapy. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of gemcitabine metabolic and transporter genes that are associated with toxicity and efficacy of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.


METHODS
The authors evaluated 17 SNPs of the CDA,dCK, DCTD, RRM1, hCNT1-3, and hENT1 genes in 149 patients with locally advanced pancreatic cancer who underwent gemcitabine-based chemoradiotherapy. The association of genotypes with neutropenia, tumor response to therapy, overall survival, and progression-free survival (PFS) was analyzed by logistic regression, log-rank test, Kaplan-Meier plot, and Cox proportional hazards regression.


RESULTS
The CDA A-76C, dCK C-1205T, RRM1 A33G, and hENT1 C913T genotypes were significantly associated with grade 3 to 4 neutropenia (P = .020, .015, .003, and .017, respectively).The CDA A-76C and hENT1 A-201G genotypes were significantly associated with tumor response to therapy (P = .017 and P = .019). A combined genotype effect of CDA A-76C, RRM1 A33G, RRM1 C-27A, and hENT1 A-201G on PFS was observed. Patients carrying 0 to 1 (n = 64), 2 (n = 50), or 3 to 4 (n = 17) at-risk genotypes had median PFS times of 8.3, 6.0, and 4.2 months, respectively (P = .002).


CONCLUSIONS
The results indicated that some polymorphic variations of drug metabolic and transporter genes may be potential biomarkers for clinical outcome of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.
Tanaka
Motofumi
M
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. dli@mdanderson.org
Javle
Milind
M
Dong
Xiaoqun
X
Eng
Cathy
C
Abbruzzese
James L
JL
Li
Donghui
D
D000368:Aged; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D018572:Disease-Free Survival; D039621:Eukaryotic Initiation Factor-3 / Q000032:analysis; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
C105988:EIF3A protein, human; D039621:Eukaryotic Initiation Factor-3; D003841:Deoxycytidine; D000093542:Gemcitabine