Class 1, 2, and 3 BRAF -Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

mutations are grouped in activating -independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and -dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of -mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Data from 117 patients with (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test. Class 3 -mutated mCRC was more frequently left sided ( = 0.0028), pN0 ( = 0.0159), and without peritoneal metastases ( = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with wt, was 2.38 [95% confidence interval (CI), 1.61-3.54] for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 ( < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in -mutated class 2 ( = 0.033) compared with class 3 cases. For the first time, different clinical and pathologic features and outcome data were reported according to the three mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.