A Further Investigation of Combined Mismatch Repair and BRAFV600E Mutation Specific Immunohistochemistry as a Predictor of Overall Survival in Colorectal Carcinoma

Abstract

Mutation specific immunohistochemistry (IHC) is a promising new technique to detect the presence of the BRAFV600E mutation in colorectal carcinoma (CRC). When performed in conjunction with mismatch repair (MMR) IHC, BRAFV600E IHC can help to further triage genetic testing for Lynch Syndrome. In a cohort of 1426 patients undergoing surgery from 2004 to 2009 we recently demonstrated that the combination of MMR and BRAFV600E IHC holds promise as a prognostic marker in CRC, particularly because of its ability to identify the poor prognosis MMR proficient (MMRp) BRAFV600E mutant subgroup. We attempted to validate combined MMR and BRAFV600E IHC as a prognostic indicator in a separate cohort comprising consecutive CRC patients undergoing surgery from 1998 to 2003. IHC was performed on a tissue microarray containing tissue from 1109 patients with CRC. The 5 year survivals stratified by staining patterns were: MMRd/BRAFwt 64%, MMRd/BRAFV600E 64%, MMRp/BRAFwt 60% and MMRp/BRAFV600E 53%. Using the poor prognosis MMRp/BRAFV600E phenotype as baseline, univariate Cox regression modelling demonstrated the following hazard ratios for death: MMRd/BRAFwt HR = 0.71 (95%CI = 0.40–1.27), p = 0.31; MMRd/BRAFV600E HR = 0.74 (95%CI = 0.51–1.07), p = 0.11 and MMRp/BRAFwt HR = 0.79 (95%CI = 0.60–1.04), p = 0.09. Although the findings did not reach statistical significance, this study supports the potential role of combined MMR and BRAF IHC as prognostic markers in CRC.

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

“…Of the studies that included patients with stage I through IV MSI CRC (Supporting Information Table ) only one reported BRAF to be significantly prognostic . Studies specifically on metastatic CRC have related the presence of BRAF mutation with worse survival within the MSI subset of CRC …”

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

“…7,21 Negative staining (MMRd/MSI) was defined as completely absent nuclear staining in the neoplastic cells in the presence of a positive internal control (Figure 1), while the MMRp/MSS pattern was defined by positive nuclear staining for all four markers in neoplastic cells (Figure 2). In our hands, we have previously demonstrated excellent concordance between immunohistochemistry interpreted on tissue microarrays and whole sections, 18 and if there was uncertainty about interpretation of the immunohistochemistry, stains were repeated on whole sections.…”

“…5) and 42% 6 of mucinous colorectal cancers have been reported to demonstrate MSI/MMRd compared with 20% or less of all unselected colorectal cancers. 7 Although some studies have reported worse survival outcomes and poorer response to chemotherapy in mucinous colorectal cancer, 8,9 to date findings have been inconsistent, with some studies showing no mortality association with mucinous histology. [10][11][12] Pathological grading of mucinous CRC is problematic.…”

Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis

“…In metastatic CRC, KRAS, NRAS and BRAF genes have already been the conventional testing indexes . Combined KRAS/BRAF‐MMR status was suggested to be prognostic for CRC outcomes in several studies . In stage II‐III CRC, a poorer survival was observed for pMMR patients with KRAS/BRAF mutations compared with wild‐type ones, while KRAS/BRAF mutations seemed to have no impact on survival outcomes for dMMR patients .…”