# Mismatch repair status and BRAF mutation status in metastatic colorectal cancer: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies

Source: https://onco.cc/key-papers/paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014/  
OnCo record `paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Pooling four large first-line trials, 3,063 patients, showed that broken DNA repair is rare in advanced bowel cancer and that the poor outlook it carries is really the poor outlook of the BRAF mutation that so often comes with it.

## Summary

A pooled analysis of four phase 3 first-line studies in metastatic colorectal cancer assessed the prevalence and prognostic value of mismatch repair status and its relation to BRAF mutation, using Cox regression on individual patient data. Of 3,063 primary tumours analysed, 153 (5.0%) showed deficient mismatch repair and 250 (8.2%) a BRAF mutation. BRAF mutation was present in 53 of 153 (34.6%) deficient tumours against 197 of 2,910 (6.8%) proficient tumours. Both markers conferred an inferior prognosis: deficient mismatch repair gave hazard ratios of 1.33 for progression-free and 1.35 for overall survival, and BRAF mutation 1.34 and 1.91. Progression-free and overall survival were significantly worse for BRAF mutation within the proficient group, but BRAF status did not separate outcomes within the deficient group, nor did mismatch repair status within either BRAF group.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Clinical Cancer Research
- Year: 2014
- DOI: 10.1158/1078-0432.CCR-14-0332
- Authors: Venderbosch S, Nagtegaal ID, Maughan TS, et al.
- Findings: Deficient mismatch repair in 153 of 3,063 (5.0%) and BRAF mutation in 250 (8.2%) first-line metastatic patients.; BRAF mutation in 34.6% of deficient against 6.8% of proficient tumours.; Overall survival hazard ratio 1.35 for deficient mismatch repair and 1.91 for BRAF mutation; the deficient penalty is driven by BRAF.
- What it means: It fixes the metastatic prevalence figures every subsequent trial design has used, and it separates two biomarkers that travel together: BRAF, not mismatch repair deficiency, is what makes the prognosis bad.
- Caveats: Predates checkpoint inhibitors, so the prognosis of deficient patients has since changed completely.; Primary tumour tissue, not metastases.; Immunohistochemistry and MSI methods differed between the four trials.

## Sources

- Venderbosch et al., Clin Cancer Res 2014: mismatch repair and BRAF status pooled across CAIRO, CAIRO2, COIN and FOCUS (3,063 patients): https://doi.org/10.1158/1078-0432.CCR-14-0332
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25139339/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/)
- targets: [BRAF](https://onco.cc/targets/braf/), [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/)
- institutions: [Leeds Cancer Centre, St James's University Hospital](https://onco.cc/institutions/leeds-cancer-centre/), [Radboudumc Centre for Oncology](https://onco.cc/institutions/radboudumc/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/)
- journals: [Clinical Cancer Research](https://onco.cc/journals/clinical-cancer-research/)
- trials: [BEACON CRC](https://onco.cc/trials/beacon-crc/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/)
- drugs: [Encorafenib](https://onco.cc/drugs/encorafenib/)
- biomarkers: [BRAF V600E (and V600K)](https://onco.cc/biomarkers/braf-v600e/), [MSI-high (microsatellite instability by PCR or sequencing)](https://onco.cc/biomarkers/msi-high/)

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