Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer: A detailed clinical, pathologic, and molecular characterization

Marta Schirripa, Paola Biason, Sara Lonardi, Nicoletta Pella, Maria Simona Pino, Federica Urbano, Carlotta Antoniotti, Chiara Cremolini, Salvatore Corallo, Filippo Pietrantonio, Fabio Gelsomino, Stefano Cascinu, Armando Orlandi, Giada Munari, Umberto Malapelle, Serena Saggio, Gabriella Fontanini, Massimo Rugge, Claudia Mescoli, Stefano LazziLuca Reggiani Bonetti, Giovanni Lanza, Angelo Paolo Dei Tos, Giovanna De Maglio, Maurizio Martini, Francesca Bergamo, Vittorina Zagonel, Fotios Loupakis, Matteo Fassan

Research output: Contribution to journalArticlepeer-review


Purpose: BRAF mutations are grouped in activating RASindependent 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 V600EBRAFmutated 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 progression-free survival were evaluated by Kaplan-Meier and log-rank test. Results: Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), pN0 (P = 0.0159), and without peritoneal metastases (P = 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 = 0.033) compared with class 3 cases. Conclusions: For the first time, different clinical and pathologic 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.
Original languageEnglish
Pages (from-to)3954-3961
Number of pages8
JournalClin. Cancer Res.
Issue number13
Publication statusPublished - Jan 1 2019


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