4126 Background: Microsatellite instability (MSI) is the hallmark of a defective DNA mismatch repair (MMR) and occurs in 10- 20 % of sporadic colorectal cancer (CRC). The loss of the MLH1 protein is the cause of MSI in almost all sporadic colorectal MSI tumours. The second most common protein to be lost is MSH2. There is evidence that MSI is a prognostic factor in CRC. The role of MSI status as a predictive factor of benefit from adjuvant 5-fluorouracil (5-FU) based chemotherapy is controversial. Methods: Monoclonal antibodies that recognize the mismatch repair protein by immunohistochemistry (IHC) have been commercially available for several years. Previous reports have found a strong correlation between MMR results obtained by immunohistochemical and genetic analysis. This study included 1006 CRC patients (488 Stage II and 518 Stage III) with a median follow-up of 5 years. The patients were included in Nordic trials randomised between surgery alone and surgery plus adjuvant 5-FU. The MMR status was retrospectively assessed on paraffin-embedded formalin-fixed samples using IHC. Results: One hundred fifty seven patients (15.6 %) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1+MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 851 patients who were defined as MMR protein positive. The median overall survival (OS) was 84 months (range 2–181 months). MMR protein expression was a significant prognostic marker in the entire study group where a better OS was seen among patients with MMR protein negative carcinomas compared to patients with MMR protein positive tumours (p=0.005). In multivariate analysis the MMR protein expression was significantly associated with OS, (hazard ratio for death, 0.67 [95 per cent confidence interval, 0.38 to 0.96]; p=0.008). However, in this study the MMR status did not predict response to 5-FU adjuvant chemotherapy. Conclusions: This study reveals that immunohistochemical analysis of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor in sporadic CRC. No significant financial relationships to disclose.
Mismatch repair protein expression in patients with stage�II and III sporadic colorectal cancer
