Fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer (CRC) is associated with a reduction of recurrence in only 25% of patients (pts) with stage III disease. The aim of this study was to investigate thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF as possible factors affecting therapeutic outcome in pts with stage III CRC.
Formalin-fixed paraffin-embedded tissues of 130 consecutive pts treated with FABC between 2005-2007 were analysed with PCR for the detection of TYMS polymorphisms, mKRAS and mBRAF. Patients were classified into three groups of 5’UTR TYMS polymorphisms according to the predicted expression profile (high, medium and low). Based on the presence or absence of the 3’UTR polymorphism ins/LOH pts were allocated into two groups (high and low risk). Cox regression models examined factors associated with survival outcome.
The 5-year DFS and OS rate was 61.6% and 73.9% respectively. Patients who had tumors with 5’UTR polymorphisms of intermediate TYMS expression profile (2RG/3RG, 2RG/LOH, 3RC/LOH) when compared to those with low (2RG/2RG, 2RG/3RC, 3RC/3RC) or high expression (3RG/3RG, 3RG/LOH, 3RG/3RC) had lower risk for relapse (HR 0.320, p = 0.02 and HR 0.343, p = 0.013 respectively) and death (HR 0.368, p = 0.031 and HR 0.394, p = 0.029 respectively). The 3’UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (p = 0.001) and death (p = 0.005). Presence of mBRAF (3.8% pts) was associated with an increased risk of death (HR 4.500, p = 0.022), whereas mKRAS (39% of pts) was not found to correlate with survival.
The group of TYMS polymorphisms 2RG/3RG, 2RG/LOH, 3RC/LOH, the absence of ins/LOH and absence of mBRAF were associated with better prognosis of pts with early stage CRC. Mutated KRAS was not found to affect relapse or risk of death in the adjuvant setting. Further prospective studies investigating the role of TYMS polymorphisms and mBRAF are warranted to identify pts who could benefit from 5FU-based cytotoxic chemotherapy.
Clinical trial identification
Legal entity responsible for the study
National and Kapodistrian University of Athens.
All authors have declared no conflicts of interest.