Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival and Drug Toxicity

Abstract

Purpose: To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2′,2′-difluoro 2′-deoxycytidine (gemcitabine)-based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.Experimental Design: We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.Results: None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.Conclusions: These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer. Clin Cancer Res; 16(1); 320-9. ©2010 AACR.2′,2′-Difluoro 2′-deoxycytidine (gemcitabine) is the standard first-line agent for treatment of pancreatic cancer. However, 75% of patients do not benefit from this therapy (1), and other than stage, it is not clear what factors predict clinical response to gemcitabine. A major dose-limiting side effect of gemcitabine is hematologic toxicity such as neutropenia and thrombocytopenia, which often result in dose reduction or longer intervals between gemcitabine administrations. However, there is no available biomarker that predicts the toxicity of gemcitabine.Gemcitabine is a nucleoside analogue and a prodrug that requires cellular uptake and intracellular phosphorylation ( Fig. 1; ref. 2). Five of the nucleotide transporters found in humans-human concentrative nucleotide transporter (hCNT) 1 to 3 (a.k.a. solute carrier family 28 A1-A3) and human equilibrative nucleotide transporter (hENT) 1 and 2 (solute carrier family 29)-seem to be responsible for cellular uptake of gemcitabine (2). Once inside the cell, gemcitabine is phosphorylated by deoxycytidine kinase (dCK) to its monophosphate form. This first stage of phosphorylation is the rate-limiting step for furth...

DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

“…However, most of our studies were limited by small sample sizes, small numbers of genes examined, and lack of validation and unknown functional significance of the genetic variants [2][3][4][5]. Thus, the potential value of our previous findings in clinical application is not yet known.…”

“…We have shown previously that genetic variations in drug metabolism and DNA repair correlate with overall survival (OS) of patients with pancreatic cancer [2][3][4][5]. However, most of our studies were limited by small sample sizes, small numbers of genes examined, and lack of validation and unknown functional significance of the genetic variants [2][3][4][5].…”

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…In fact other studies have not found an association between this CDA Lys 27 Gln polymorphism and treatment outcome after treatment with nucleoside analogs. 5,6 One limitation of our study is the absence of more detailed information on the individual events and frequencies contributing to the severe hematological toxicity, including whether or not they were asymptomatic or contributed to dose modification or treatment delay.…”

“…4 However, other data does not find an association between this CDA polymorphism and treatment outcome with gemcitabine. 5,6 The Radiation Therapy Oncology Group (RTOG) 9704 study is a phase III randomized post-operative adjuvant study in patients after resection of pancreatic cancer comparing pre-and post-chemoradiation 5-FU with preand post-chemoradiation 5-fluororuacil and gemcitabine. 7 It represents a unique tool to validate markers predictive of gemcitabine treatment response and toxicity.…”

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

“…Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”