Microsatellite Instability (MSI) and BRAF Mutation Tests Jointly Provide Useful Prognostic Information in 1861 Colorectal Cancers
Paul Lochhead, Charles Fuchs, Shuji Ogino. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA
Background: Microsatellite instability (MSI) and BRAF mutation analyses have become routine in the workup of colorectal cancers. For prognostication of all colorectal cancer patients, we examined the prognostic utility of combined MSI/BRAF status, and statistically assessed whether MSI status (or BRAF status) modified prognostic association of BRAF status (or MSI status).
Design: We examined molecular features and survival in 1861 colorectal cancers, including 1253 stage I-IV colorectal cancers (cohort A) and a validation set of 608 stage III colon cancers in phase III clinical trial (cohort B). BRAF status was assessed by Pyrosequencing, and MSI status was determined using 10 microsatellite markers. Cox proportional hazards models were used to compute mortality hazard ratio (HR), adjusting for clinical, pathologic and other molecular features, including KRAS status.
Results: In both cohorts, the poorest colorectal cancer-specific survival was experienced by patients with microsatellite stable (MSS)/BRAF-mutant cancer, and the best survival by patients with MSI-high/BRAF-wild-type cancer in Kaplan-Meier analyses.
In both cohorts, multivariate survival analyses demonstrated that MSS/BRAF-mutant was the least favorable subtype, while MSI-high/BRAF-wild-type was the most favorable subtype.
|MSI status||BRAF status||Cohort A (N=1253)||Cohort B (N=608)|
|Multivariate HR (95% CI)||P value||Multivariate HR (95% CI)||P value|
|MSS||Mutant||1 (reference)||1 (reference)|
|MSS||Wild-type||0.63 (0.44-0.89)||<0.001||0.67 (0.43-1.04)||0.074|
|MSI-high||Mutant||0.30 (0.16-0.58)||<0.001||0.67 (0.35-1.26)||0.22|
|MSI-high||Wild-type||0.16 (0.07-0.35)||<0.001||0.48 (0.26-0.90)||0.022|