Association between single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC) and clinical outcomes in advanced gastric cancer (AGC) patients (pts) treated with taxane-based chemotherapy.

Abstract

79 Background: Taxanes which disrupt the microtubule function and inhibit the process of cell division have shown encouraging activity in the treatment of AGC. Resistance to these agents often becomes a problem in clinical settings and its mechanism hasn’t been dissolved conclusively. SAC is a safety device ensures the proper chromosome segregation in mitosis and is required for taxane-induced cell death. We hypothesized genetic variants in SAC genes may be associated with clinical outcomes in pts with AGC treated with taxane. Methods: Genomic DNA was isolated from blood or tissue samples of 39 U.S. pts (median age 57; median follow-up 6.4 months) for evaluation set and 39 Japanese (JPN) pts (median age 63; median follow-up 9.4 months) for validation set, with AGC treated with taxane. Twenty-five functionally significant SNPs in SAC genes (MAD1, MAD2, BUB3, BUBR1, RAN, TPX2, CDC20, AURKA, AURKB, RCC1, ANAPC10, ANAPC13) were analyzed by PCR-based direct sequencing and evaluated for association with outcomes. Results: In univariate analysis, rs4236271 (MAD1), rs6954673 (MAD1), and rs2064863 (AURKA) showed a significant difference in 6-month (mo) progression-free survival (PFS) rate [(C/C 42%, C/T 12%; HR 2.66, P=0.008), (C/C 75%, C/T or T/T 24%; HR 5.10, P=0.008), and (T/T 50%, T/G 15%, G/G 57%; HR1.55, P=0.046), respectively] and 18-mo overall survival (OS) rate [(C/C 40%, C/T 8%; HR3.69, P<0.001), (C/C 56%, C/T or T/T 19%; HR3.60, P=0.004), and (T/T 59%, T/G 15%, G/G 29%; HR 2.02, P=0.047), respectively] in evaluation set. In multivariate analysis, rs4236271 and rs6954673 remained significant in PFS (HR 7.24, P=0.005, HR 14.49, P=0.015, respectively) and OS (HR 7.39, P=0.001, HR 6.37, P=0.002, respectively). In validation set, rs6954763 showed a significant difference in 18-mo OS rate (C/C 16%, C/T or T/T 47%, HR 3.55, P=0.014), but the impact of C/C genotype on OS in the JPN pts was the opposite to the U.S. pts. Conclusions: These results suggest that MAD1 polymorphisms may serve as a prognostic marker in pts with AGC. Further studies using larger population are needed to corroborate our results.