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 journalArticle

3 Citations (Scopus)

Abstract

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
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
Publication statusPublished - Jan 1 2019

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Colorectal Neoplasms
Confidence Intervals
Codon
Keratin-20
CD8-Positive T-Lymphocytes
Keratin-7
Tumor-Infiltrating Lymphocytes
Mutation
Survival
Disease-Free Survival
Research Design
Phosphotransferases
Neoplasm Metastasis
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer : A detailed clinical, pathologic, and molecular characterization. / Schirripa, Marta; Biason, Paola; Lonardi, Sara; Pella, Nicoletta; Simona Pino, Maria; Urbano, Federica; Antoniotti, Carlotta; Cremolini, Chiara; Corallo, Salvatore; Pietrantonio, Filippo; Gelsomino, Fabio; Cascinu, Stefano; Orlandi, Armando; Munari, Giada; Malapelle, Umberto; Saggio, Serena; Fontanini, Gabriella; Rugge, Massimo; Mescoli, Claudia; Lazzi, Stefano; Bonetti, Luca Reggiani; Lanza, Giovanni; Dei Tos, Angelo Paolo; De Maglio, Giovanna; Martini, Maurizio; Bergamo, Francesca; Zagonel, Vittorina; Loupakis, Fotios; Fassan, Matteo.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 3954-3961.

Research output: Contribution to journalArticle

Schirripa, M, Biason, P, Lonardi, S, Pella, N, Simona Pino, M, Urbano, F, Antoniotti, C, Cremolini, C, Corallo, S, Pietrantonio, F, Gelsomino, F, Cascinu, S, Orlandi, A, Munari, G, Malapelle, U, Saggio, S, Fontanini, G, Rugge, M, Mescoli, C, Lazzi, S, Bonetti, LR, Lanza, G, Dei Tos, AP, De Maglio, G, Martini, M, Bergamo, F, Zagonel, V, Loupakis, F & Fassan, M 2019, 'Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer: A detailed clinical, pathologic, and molecular characterization', Clinical Cancer Research, vol. 25, no. 13, pp. 3954-3961. https://doi.org/10.1158/1078-0432.CCR-19-0311
Schirripa, Marta ; Biason, Paola ; Lonardi, Sara ; Pella, Nicoletta ; Simona Pino, Maria ; Urbano, Federica ; Antoniotti, Carlotta ; Cremolini, Chiara ; Corallo, Salvatore ; Pietrantonio, Filippo ; Gelsomino, Fabio ; Cascinu, Stefano ; Orlandi, Armando ; Munari, Giada ; Malapelle, Umberto ; Saggio, Serena ; Fontanini, Gabriella ; Rugge, Massimo ; Mescoli, Claudia ; Lazzi, Stefano ; Bonetti, Luca Reggiani ; Lanza, Giovanni ; Dei Tos, Angelo Paolo ; De Maglio, Giovanna ; Martini, Maurizio ; Bergamo, Francesca ; Zagonel, Vittorina ; Loupakis, Fotios ; Fassan, Matteo. / Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer : A detailed clinical, pathologic, and molecular characterization. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 3954-3961.
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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.

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