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

Abstract

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 crosscomplementing1 (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 (677C!T, Ala!Val mutation) and XRCC1 gene (Arg!Gln 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.

Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

“…18 Additionally, reports in colorectal cancer patients show an improved survival for patients with XRCC1-399 G allele receiving 5-FU/oxaplatin chemotherapy. 19 Similar results were demonstrated in lung cancer, 20 breast cancer 21 and esophageal cancer. 22 Only one recent study has been published, supporting the pharmacogenetic role of XRCC1-399 polymorphism in gastric cancer patients.…”

Single nucleotide polymorphisms in glutathione S-transferase P1 and M1 genes and overall survival of patients with ovarian serous cystadenocarcinoma treated with chemotherapy

“…In addition, patients that were GSTP1 heterozygous carriers of the valine allele (A/G) had an increased risk of mortality, which is contrary to the results of other studies (33,34).…”

Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice

“…It interacts with other proteins involved in several stages of BER pathways, including repairing specific base damage caused by oxaliplatin (Moreno et al, 2006). Suh et al (2006) showed that XRCC1 Arg399Gln was a significant predictive factor for the response to FOLFOX chemotherapy and short-term survival in Asian mCRC patients.…”