Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer

Abstract

Background: It is hypothesized that BRAF mutant cancers represent a discrete subset of metastatic colorectal cancer (CRC) defined by poorer survival. This study investigates whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread and explores the impact of BRAF mutation and microsatellite instability (MSI) on prognosis in metastatic CRC.

Methods: By using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center), patients with known BRAF mutation status were analyzed for clinical characteristics, survival, and metastatic sites.

Results: The authors identified 524 metastatic CRC patients where BRAF mutation status was known; 57 (11%) were BRAF mutant tumors. BRAF mutant tumors were significantly associated with right-sided primary tumor, MSI, and poorer survival (median, 10.4 months vs 34.7 months, P < .001). A distinct pattern of metastatic spread was observed in BRAF mutant tumors, namely higher rates of peritoneal metastases (46% vs 24%, P = .001), distant lymph node metastases (53% vs 38%, P = .008), and lower rates of lung metastases (35% vs 49%, P = .049). In additional survival analyses, MSI tumors had significantly poorer survival compared with microsatellite stable tumors (22.1 months vs 11.1 months, P = .017), but this difference was not evident in the BRAF mutant population.

Conclusions: The pattern of metastatic spread observed in this study further defines BRAF mutant CRC as a discrete disease subset. The authors demonstrated that, unlikely early stage disease, MSI is associated with poorer survival in metastatic CRC, although this is driven by its association with BRAF mutation.

Figure 1a

Overall Survival: BRAF mutant tumors versus BRAF wild-type tumors

Figure 1b

Overall Survival: BRAF mutant tumors versus BRAF wild-type tumors in population-based cohort

Figure 1c

Overall Survival: BRAF mutant tumors versus BRAF wild-type tumors in trial-screened cohort

Figure 1d

Overall survival: RMH versus MDACC

Figure 2a

Overall Survival: MSS tumors versus MSI tumors

Figure 2b

Overall Survival: MSS versus MSI in BRAF mutant tumors

Figure 2c

Overall Survival: MSS versus MSI in BRAF wild-type tumors

Figure 2d

Overall Survival: BRAF mutant versus BRAF wild-type in MSI tumors

Figure 2e

Overall Survival: BRAF mutant versus wild-type in MSS tumors