TY - JOUR
T1 - Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer
T2 - A detailed clinical, pathologic, and molecular characterization
AU - Schirripa, Marta
AU - Biason, Paola
AU - Lonardi, Sara
AU - Pella, Nicoletta
AU - Simona Pino, Maria
AU - Urbano, Federica
AU - Antoniotti, Carlotta
AU - Cremolini, Chiara
AU - Corallo, Salvatore
AU - Pietrantonio, Filippo
AU - Gelsomino, Fabio
AU - Cascinu, Stefano
AU - Orlandi, Armando
AU - Munari, Giada
AU - Malapelle, Umberto
AU - Saggio, Serena
AU - Fontanini, Gabriella
AU - Rugge, Massimo
AU - Mescoli, Claudia
AU - Lazzi, Stefano
AU - Bonetti, Luca Reggiani
AU - Lanza, Giovanni
AU - Dei Tos, Angelo Paolo
AU - De Maglio, Giovanna
AU - Martini, Maurizio
AU - Bergamo, Francesca
AU - Zagonel, Vittorina
AU - Loupakis, Fotios
AU - Fassan, Matteo
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-19-0311
DO - 10.1158/1078-0432.CCR-19-0311
M3 - Article
VL - 25
SP - 3954
EP - 3961
JO - Clin. Cancer Res.
JF - Clin. Cancer Res.
SN - 1078-0432
IS - 13
ER -