[688] 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.

Combined MSI/BRAF subtypes and mortality in colorectal cancer
MSI statusBRAF statusCohort A (N=1253) Cohort B (N=608) 
  Multivariate HR (95% CI)P valueMultivariate HR (95% CI)P value
MSSMutant1 (reference) 1 (reference) 
MSSWild-type0.63 (0.44-0.89)<0.0010.67 (0.43-1.04)0.074
MSI-highMutant0.30 (0.16-0.58)<0.0010.67 (0.35-1.26)0.22
MSI-highWild-type0.16 (0.07-0.35)<0.0010.48 (0.26-0.90)0.022
CI, confidence interval; HR, hazard ratio

In both cohorts, there was no significant interaction between MSI and BRAF mutation in survival analyses (all Pinteraction>0.50), suggesting independent roles of MSI and BRAF status in survival analyses.
Conclusions: MSI and BRAF mutation tests in colorectal cancer can jointly provide useful prognostic information. MSI-high/BRAF-wild-type is the most favorable group, while MSS/BRAF-mutant is the least favorable group, and MSI-high/BRAF-mutant and MSS/BRAF-wild-type are intermediate groups.
Category: Gastrointestinal

Wednesday, March 6, 2013 9:30 AM

Poster Session V # 96, Wednesday Morning


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