Demystifying BRAF Mutation Status in Colorectal Liver Metastases A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions

Objective:To investigate the clinical implications of BRAF-mutated (mutBRAF) colorectal liver metastases (CRLMs). Background:The clinical implications of mutBRAF status in CRLMs are largely unknown. Methods:Patients undergoing resection for mutBRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mutBRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. Results:A total of 240 patients harboring BRAF-mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P=0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P<0.001) but not OS (33.5 vs 41 mo, P=0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P=0.01) and similar OS (30 vs 40 mo, P=0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P<0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P=0.004). All results continued to hold true in the multivariable OS analysis. Conclusions:Although surgery may be futile in patients with BRAF-mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.