Abstract LB-24: Association between drug metabolizing and DNA-repair enzyme polymorphisms and overall survival of colorectal cancer patients treated with 5-FU based adjuvant chemotherapy in Taiwan.

Abstract

Abstract Background: In Taiwan, 42% metastatic colorectal cancer (CRC) patients are frequently administered adjuvant chemotherapy in order to reduce the probability of tumor recurrence and prolong survival years after surgery. The treatment mainstay for CRC characterized with inter-individual variation in activities of drug metabolizing enzymes and DNA-repair capacity, may modulate the chemotherapeutic outcome in CRC patients. This retrospective cohort study investigated the association among drug metabolizing, DNA-repair enzymes genetic polymorphisms and overall survival in CRC patients treated with 5-fluorouracil (5-FU) based adjuvant hemotherapy. Method: To continue previous preliminary study, we recruited 2716 consecutive patients with newly diagnosed and histologically confirmed CRC from the Chang Gung Memorial Hospital between 1995 and 2001. We genotyped polymorphisms of 3 metabolizing genes (GSTM1, GSTT1, and GSTP1 Ile105Val) and 3 DNA-repair genes (XRCC1 Arg399Gln, XRCC3 Thr241Met,and XPD Lys751Gln) in 499 patients who had received postoperative chemotherapy. Cox proportional hazard models were used to calculate the Hazard ratios (HRs) and 95% confidence intervals (CIs). Survival analyses were performed using log-rank test and Kaplan-Meier curve. Results: In the study patients, mean age was 58 years (SD=12.4), 234 (47.1%) were women, and 211 (42.3%) had rectal cancer. Four hundred ninety-nine CRC patients were assessable for overall survival, the median follow-up period was 48.8 months (range 1.4 - 133.3 months). After adjusting for age and TNM stage, patients carrying the XPD Lys/Gln+Gln/Gln genotype had poorer survival than in patients with the XPD Lys/Lys genotype (HR=1.38, 95% CI=1.02-1.87). Furthermore, the XPD Lys/Gln genotype (HR=1.80, 95% CI=1.15-2.81) were also significantly associated with a short survival in rectal cancer patients. Combination analysis with the GSTT1, XPD, TNM stage, gender, and age in multivariable models revealed that the significant HRs for elder, TNM stage III, IV, XPD Lys/Gln, and GSTT1 null genotype were 1.02, 2.78, 17.0, 1.38, and 1.29, respectively Conclusion: The results suggest that polymorphisms of XPD Lys751Gln may be prognostic markers for predicting overall survival of CRC patients who receive 5-FU based adjuvant chemotherapy. Citation Format: Ching-Yu Lai, Fung-Chang Sung, Ling-Ling Hsieh, Reiping Tang, Fang-Yang Wu, Hung-Yi Chiou, Chih-Ching Yeh. Association between drug metabolizing and DNA-repair enzyme polymorphisms and overall survival of colorectal cancer patients treated with 5-FU based adjuvant chemotherapy in Taiwan. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-24. doi:10.1158/1538-7445.AM2013-LB-24