Class 1, 2, and 3 <i>BRAF</i>-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization.

Abstract

<i>BRAF</i> mutations are grouped in activating <i>RAS</i>-independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and <i>RAS</i>-dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of <i>^V600EBRAF</i>-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Data from 117 patients with <i>BRAF</i> (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 <i>BRAF</i> 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 <i>BRAF</i>-mutated mCRC was more frequently left sided (<i>P</i> = 0.0028), pN0 (<i>P</i> = 0.0159), and without peritoneal metastases (<i>P</i> = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with <i>BRAF</i> 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 (<i>P</i> < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in <i>BRAF</i>-mutated class 2 (<i>P</i> = 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 <i>BRAF</i> mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.