Prognostic Role of Combined MSI and BRAF Mutation Status in Colorectal Cancer: Toward Routine Clinical Use
Jeanne Shen, Teppei Morikawa, Charles S Fuchs, Shuji Ogino. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA
Background: Microsatellite instability (MSI) analysis and BRAF sequencing are becoming routine clinical tests for colorectal cancer (CRC) prognostication and familial risk assessment. Although MSI-high [MSI-H] has been associated with good prognosis and BRAF mutation with poor prognosis, it remains uncertain whether MSI-H (or BRAF mutation) influences clinical outcome independently of BRAF (or MSI) status. To clarify the prognostic roles of MSI and BRAF status, a large sample is required for adequate statistical power, because BRAF mutations and MSI-H exist in a minority of CRCs.
Design: The relationship between MSI and BRAF status and patient survival was analyzed in 1343 CRCs. The Cox proportional hazards model was used to compute mortality hazard ratios (HRs) according to combined MSI/BRAF status, adjusting for potential confounders, including disease stage.
Results: MSI-H was detected in 15% and BRAF mutation in 14% of CRCs, respectively. The percentages for the combined MSI-BRAF subtypes were: MSI-H BRAF-mutated [mut], 8%; MSI-H BRAF-wildtype [wt], 7%; MSS (non-MSI-H) BRAF-mut, 6%; and MSS BRAF-wt, 79%. Using MSS BRAF-mut as the reference group, the multivariate HRs (95% confidence interval [CI]) for CRC-specific mortality were: MSI-H BRAF-wt, 0.19 (0.09, 0.41); MSI-H BRAF-mut, 0.41 (0.22, 0.77); and MSS BRAF-wt, 0.56 (0.39, 0.80). HRs (95% CI) for overall mortality were: MSI-H BRAF-wt, 0.47 (0.29, 0.74); MSI-H BRAF-mut, 0.74 (0.48, 1.14); and MSS BRAF-wt, 0.68 (0.49, 0.93). Kaplan-Meier analysis showed that survival was lowest for the MSS BRAF-mut patients, and highest for the MSI-H BRAF-wt patients (p < .0001 for CRC-specific and p = .0003 for overall mortality.
No significant interaction was present between MSI and BRAF (p=0.52), indicating that the prognostic role of MSI-H (or BRAF mutation) was independent of BRAF (or MSI) status.
Conclusions: By combined MSI/BRAF subtyping, MSI-H BRAF-wt patients have the best prognosis, whereas MSS BRAF-mut patients have the worst. Thus, the routine clinical use of both MSI and BRAF testing to subclassify patients will aid prognostication, resulting in better-informed clinical decision making and improved patient care.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 103, Monday Morning