Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

Venderbosch, Sabine; Nagtegaal, Iris D.; Maughan, Tim S.; Smith, Christopher G.; Cheadle, Jeremy P.; Fisher, David; Kaplan, Richard; Quirke, Philip; Seymour, Matthew T.; Richman, Susan D.; Meijer, Gerrit A.; Ylstra, Bauke; Heideman, Danielle A.M.; de Haan, Anton F.J.; Punt, Cornelis J.A.; Koopman, Miriam

doi:10.1158/1078-0432.ccr-14-0332

Cited by 772Colorectal Cancer Treatments and StudiesGenetic factors in colorectal cancerColorectal Cancer Surgical Treatments

Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

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Venderbosch, Sabine, Nagtegaal, Iris D., Maughan, Tim S., Smith, Christopher G., Cheadle, Jeremy P., Fisher, David, Kaplan, Richard, Quirke, Philip +8 more·2014·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-14-0332PMC PMC4201568

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Abstract

Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAFMT) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data. Results: The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAFMT. BRAFMT was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P < 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors [HR, 1.33; 95% confidence interval (CI), 1.12–1.57 and HR, 1.35; 95% CI, 1.13–1.61, respectively), and for patients with BRAFMT compared with BRAF wild-type (BRAFWT) tumors (HR, 1.34; 95% CI, 1.17–1.54 and HR, 1.91; 95% CI, 1.66–2.19, respectively). PFS and OS were significantly decreased for patients with BRAFMT within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAFWT or BRAFMT. Conclusions: Prevalence of dMMR and BRAFMT in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAFMT status. Clin Cancer Res; 20(20); 5322–30. ©2014 AACR.

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In four metastatic colorectal cancer studies, 21% of BRAFV600E-positive cases were also MSI-H/dMMR, while 35% of MSI-H/dMMR cases were BRAFV600E-positive.
“Recent research of four mCRC studies revealed that 21% of BRAFV600E(+) cases were also MSI-H/dMMR, while 35% of MSI-H/dMMR cases were BRAFV600E(+) [40].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [40]

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Authors: Venderbosch, S., Nagtegaal, I. D., Maughan, T. S., Smith, C. G., Cheadle, J. P., Fisher, D., Kaplan, R., Quirke, P., Seymour, M. T., Richman, S. D., Meijer, G. A., Ylstra, B., Heideman, D. A. M., de Haan, A. F. J., Punt, C. J. A., & Koopman, M.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
1Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
University of Oxford (GB)
Cardiff University (GB)
Medical Research Council (GB)
St James's University Hospital (GB)
7Department of Medical Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
8Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
9Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
University Medical Center Utrecht (NL)
Corresponding author: Koopman, Miriam
ORCID: Maughan, Tim S.
Cheadle, Jeremy P.
Fisher, David
Kaplan, Richard
Quirke, Philip
Richman, Susan D.
Meijer, Gerrit A.
Ylstra, Bauke
Punt, Cornelis J.A.
Koopman, Miriam
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2014-10-14
Volume: 20
Issue: 20
Pages: 5322-5330
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-14-0332
PMC: PMC4201568
OpenAlex: W2159064822
Cited by: 772
References: 43
Citations by year: 2026: 44 · 2025: 60 · 2024: 87 · 2023: 95 · 2022: 88 · 2021: 100 · 2020: 84 · 2019: 74 · 2018: 50 · 2017: 37 · 2016: 30 · 2015: 18 · 2014: 2
FWCI: 13.91
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Funders: Cancer Research UK (A4850)
Medical Research Council (MR/L01629X/1)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
Keywords: mismatch repair deficiency, BRAF mutation, metastatic colorectal cancer, prognostic factors, progression-free survival, overall survival, first-line therapy, microsatellite instability, individual patient data pooling
MeSH terms: MutL Protein Homolog 1, Humans, Mutation, Neoplasm Metastasis, Nuclear Proteins, Prognosis, Promoter Regions, Genetic, Colorectal Neoplasms, Case-Control Studies, Clinical Trials, Phase III as Topic, DNA Methylation, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, DNA Mismatch Repair

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Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

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