The Joint Value Of Microsatellite Instability And The Braf V600E Mutation In Colorectal Cancer Prognosis

Colinda SIMONS, Maastricht University, Netherlands
VAN DEN BRANDT P. 1 , VAN ENGELAND M. 2 , WEIJENBERG M. 1

1 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
2 Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands

Purpose: While microsatellite instability (MSI) is a favorable prognostic marker in colorectal cancer (CRC), the BRAF V600E mutation may predict worse survival in microsatellite stable (MSS) and MSI tumors. We aimed to replicate and summarize associations between MSI/BRAF status and mortality in literature.
Methods: Cox regression analyses were adjusted for clinically relevant covariates and included 530 CRC cases from the Netherlands Cohort Study, diagnosed during 1989–1993, with follow-up until December 31, 2009. 366 cases died, including 207 of CRC-related deaths. We pooled mortality hazard ratios with those from previous studies and made three different comparisons (model 1–3). P <0.05 indicated statistical significance.
Results: The first model included MSI/BRAF combinations and showed, compared to MSS BRAF wild type tumors, an increased CRC-specific mortality risk for MSS BRAF mutated tumors [pooled HR (95% confidence interval, CI) = 1.59 (1.34 to 1.89)], while risk was decreased for MSI BRAF wild type and mutated tumors [pooled HRs (95% CIs) = 0.43 (0.29 to 0.63) and 0.64 (0.49 to 0.85), respectively]. Comparison of BRAF mutated with wild type tumors within MSS tumors (the second model) and MSI tumors (the third model) showed increased CRC-specific mortality risks, although these were nonsignificant within MSI tumors [pooled HRs (95% CIs) = 1.55 (1.30 to 1.86) and 1.43 (0.88 to 2.32), respectively]. Associations extended to overall mortality within MSS tumors.
Conclusions: MSI overrides BRAF status in prognosis, but the BRAF mutation was associated with worse survival within MSS and, possibly, MSI tumors. This justifies research on interventions that could benefit MSI/BRAF subgroups.
Funding source: World Cancer Research Fund; Health Foundation Limburg.