Objectives: Many primary studies have considered the association of polymorphisms of folate metabolism and response to 5-fluorouracil (5-FU) and capecitabine in patients with colorectal cancer. The conclusions from these studies have been conflicting and few have considered large cohorts of patients. Therefore, we have completed a systematic review and meta-analyses to summarize some of the findings to date. We conducted searches for any studies that had addressed the prognostic value of genotype analysis of thymidylate synthetase (TYMS), Methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR).
Methods: We collected data on the study designs, and completed meta-analyses to pool congruent data about treatment effect. A narrative summary is presented for 39 studies that describe three TYMS genotypes and two MTHFR genotypes associated with response to 5-FU-based chemotherapy.
Results: Data were synthesized from up to 2402 patients for the most commonly studied markers TYMS 5' UTR repeat polymorphism (rs45445694) and MTHFR 677 C>T (rs1801133). We found that the TYMS genotype associated with the lowest protein expression (2R/2R) was significantly associated with improved clinical benefit; the pooled risk ratio was relative risk=1.36 [1.11, 1.65]; P=0.003. Moreover, the same trend was observed for adverse effects; the pooled risk ratio was 2.04 [1.42, 2.95]; P=0.0001.
Conclusion: There is a small but statistically significant association between treatment effect (both intended effects and adverse events) and a TYMS genotype associated with low protein expression; however, the effect size is small and therefore indicates limited clinical utility.