Combined Microsatellite Instability and BRAF Status a Potential Marker of Risk Stratification in Colorectal Cancer
In a study reported in Journal of the National Cancer Institute, Paul Lochhead, MBChB,MRCP, of the Dana-Farber Cancer Institute and Harvard Medical School, and colleagues analyzed the association of microsatellite instability and BRAF status subgroups with survival in patients with colorectal cancer. They found that combined microsatellite instability/BRAF status is a potential biomarker for prognostic risk stratification.
Study Details
In the study, the association of combined microsatellite instability/BRAF subgroups with survival was analyzed in 1,253 patients with rectal and colon cancer from the Nurses’ Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. During median follow-up of 8.2 years, there were 608 deaths, including 361 colorectal cancer–specific deaths.
Associations With Microsatellite Instability and BRAF Status
On multivariable analyses, BRAF mutation was significantly associated with higher colorectal cancer–specific mortality (hazard ratio [HR] = 1.64, P = .003). Microsatellite instability–high status was significantly associated with lower colorectal cancer–specific mortality (HR = 0.28, P < .001). Microsatellite instability status was a confounder for BRAF mutation; after adjustment for microsatellite instability status, the colorectal cancer–specific hazard ratio for BRAF mutation was 2.05 (compared with a univariate hazard ratio estimate of 1.14).
On multivariable analysis, increased colorectal cancer–specific mortality appeared to be associated with BRAF mutation in both microsatellite stable (HR = 1.60, P = .009) and microsatellite instability–high tumor strata (HR = 1.90, P = .15). Lower colorectal cancer–specific mortality was significantly associated with microsatellite instability–high in both BRAF wild-type (HR = 0.25, P < .001) and BRAF mutant strata (HR = 0.30, P < .001).
Associations With Combined Subgroups
For combined microsatellite instability/BRAF subgroups, 5-year colorectal cancer–specific survival was 46% for microsatellite stable/BRAF mutant, 65% for microsatellite stable/BRAF wild-type, 73% for microsatellite instability–high/BRAF mutant, and 79% for microsatellite instability–high/BRAF wild-type groupings (P < .001). In multivariable analyses, compared with the majority subtype of microsatellite stable/BRAF wild-type, colorectal cancer–specific mortality hazard ratios were significantly increased for microsatellite stable/BRAF mutant (1.60, P = .009) and significantly reduced for microsatellite instability–high/BRAF mutant (0.48, P= .02) and microsatellite instability–high/BRAF wild-type (0.25, P < .001). There was no evidence of interaction between microsatellite instability and BRAF status in the survival models (all P > .50 for interaction).
The authors noted that their findings are consistent with previous studies indicating that microsatellite instability–high status is associated with favorable outcome and BRAF mutation is associated with poor survival, and they stated that the finding of favorable prognosis for microsatellite instability–high/BRAF mutant tumors compared with microsatellite stable/BRAF wild-type tumors needs to be confirmed in other populations.
The investigators concluded: “[O]ur data support a prognostic role for combined [microsatellite instability]/BRAF testing in colorectal cancer. Future studies should examine the predictive role of [microsatellite instability]/BRAF classification for response to therapeutic and lifestyle interventions.”
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