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Which Gene is a Dominant Predictor of Response During FOLFOX Chemotherapy for the Treatment of Metastatic Colorectal Cancer, the MTHFR or XRCC1 Gene?

¹ Department of Surgery, Ajou University School of Medicine, Suwon, 442-749, Korea
² Department of Pathology, Ajou University School of Medicine, Suwon, Korea
³ ISU ABIXIS Co., Ltd., Seoul, Korea

Correspondence: Address correspondence and reprint requests to: Kwang Wook Suh, MD; E-mail: suhkw{at}ajou.ac.kr

Background: Combination chemotherapy using oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX) is known to be effective in the treatment of metastatic colon cancer. Genes regulating the actions of 5-fluorouracil and oxaliplatin have been identified, but precisely which gene is dominant has not yet been determined. The aim of the investigation reported here was to identify which gene polymorphism is a dominant factor in FOLFOX chemotherapy–the methylenetetrahydrofolate reductase (MTHFR) gene for 5-fluorouracil or the X-ray cross-complementing1 (XRCC1) gene for oxaliplatin.

Methods: Paraffin-embedded tissues from 54 patients with unresectable metastases from colorectal cancer who had undergone chemotherapy with the FOLFOX regimen were analyzed for MTHFR polymorphisms in the MTHFR gene (677CT, AlaVal mutation) and XRCC1 gene (ArgGln substitution in exon 10). Response rates and survivals were compared by types of polymorphism.

Results: Analyses of the patterns of MTHFR polymorphism revealed that 29.6% of the patients showed no mutation, 51.6% showed heterozygous mutations, and 11.8% showed homozygous mutations. Analyses of the XRCC1 polymorphism revealed that 60.8% of the patients showed no mutation, 31.4% showed heterozygous mutations, and 7.8% showed homozygous mutations. After four cycles of chemotherapy, 3.7% showed a complete response, 57.4% showed a partial response (PD) or stable disease, and 38.9% showed PD. The MTHFR polymorphism was not significant in predicting response and 30-month-survival (P > 0.1), whereas the XRCC1 polymorphism was a significant prognostic factor for both response (P = 0.038) and survival (P = 0.011).

Conclusions: We found a higher rate of mutations in the MTHFR gene than in the XRCC1 gene in Korean colorectal cancer patients. Response to FOLFOX was better in the patient group with mutations for MTHFR and worse in the patient group with mutations for XRCC1. However, only the XRCC1 polymorphism was a significant prognostic factor for the response to FOLFOX chemotherapy and short-term survival.

Key Words: Metastatic colon cancer • FOLFOX • XRCC1 • MTHFR • Gene polymorphism

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