Class 1, 2, and 3 BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, 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). Although
clinical, pathologic, and molecular features of V600EBRAF mutated metastatic colorectal cancer (mCRC) are well known,
limited data are available from the two other classes.
Experimental Design: Data from 117 patients with BRAF
(92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were
collected. A total of 540 BRAF 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 pro gression-free survival were evaluated by Kaplan–Meier and
log-rank test.
Results: Class 3 BRAF-mutated mCRC was more frequently
left sided (P ¼ 0.0028), pN0 (P ¼ 0.0159), and without
peritoneal metastases (P ¼ 0.0176) compared with class 1,
whereas class 2 cases were similar to class 1. Hazard ratio for
OS, as compared with BRAF 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
(P < 0.0001). Class 2 and 3 tumors were all assigned to
CMS2-3. A higher median CD3/CD8-positive lymphocyte
infiltration was observed in BRAF-mutated class 2 (P ¼
0.033) compared with class 3 cases.
Conclusions: For the first time, different clinical and path ologic features and outcome data were reported according to
the three BRAF mutation classes in mCRC. Specific targeted
treatment strategies should be identified in the near future for
such patients.