Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: a detailed clinical, pathological and molecular characterization

Purpose BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1 - V600E) or as dimers (class 2 - codons 597/601), and RAS-dependent with impaired kinase activity (class 3 - codons 594/596). While clinical, pathological and molecular features of V600E BRAF mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design Data from 117 BRAF (92 class 1, 12 class 2, and 13 class 3) mutated mCRC patients were collected. 540 BRAF wt mCRC were included as control. Immunohistochemical profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratins 7/20 profiles, tumor infiltrating lymphocytes (TILs) infiltration and BM1/BM2 categorization. OS and PFS were evaluated by Kaplan-Meier and log-rank test. Results Class 3 BRAF mutated mCRC were more frequently left sided (p=0.0028), pN0 (p=0.0159), and with no peritoneal metastases (p=0.0176) compared to class 1, whereas class 2 cases were similar to class 1. HR for OS, as compared to BRAF wt, was 2.38 (95%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 (p<0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8 positive lymphocytes infiltration was observed in BRAF mutated class 2 (p= 0.033) compared to class 3 cases. Conclusions For the first time different clinical, pathological features and outcome data are reported according to the 3 BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the next future for such patients.