Prognostic significance of xCT gene single nucleotide polymorphisms (SNPs) in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (GEM) plus platinum analogues (PLAT).

Abstract

4065 Background: The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by PC cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including PLAT. Methods: We have investigated the relationship between xCT gene SNPs and overall survival (OS) of pts with PC treated with GEM ± PLAT. We examined 4 SNPs of the xCT gene in 269 advanced PC pts who received first line GEM with or without cisplatin or oxaliplatin. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping was performed using Taqman real-time PCR assays. The association between SNPs and OS was analyzed by Kaplan-Meier plot, log-rank test and Cox proportional hazard regression models and corrected for previously identified prognostic factors, including CA 19-9, stage, and performance status. Results: A statistically significant correlation was noted between the 3’ untranslated region (UTR) xCT SNP rs7674870 and OS: Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in pts receiving GEM+PLAT therapy (n = 145): MST was 10.5 vs. 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). This effect remained statistically significant after adjusting for clinical factors (hazard ratio: 0.60, 95% CI, 0.40-0.89 and p = 0.011). The genotype effect was not significant in pts receiving GEM alone (n = 124): MST was 10.9 months for TT and 12.0 months for TC/CC genotypes (p = 0.47). None of the 3 synonymous SNPs examined were associated with outcome. Conclusions: The 3’ UTR xCT SNP rs7674870 may correlate with OS in PC pts receiving GEM+PLAT therapy. These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in PC. No significant financial relationships to disclose.