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. 2014 Oct 15;20(20):5322-30.
doi: 10.1158/1078-0432.CCR-14-0332. Epub 2014 Aug 19.

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

Sabine Venderbosch  1 , Iris D Nagtegaal  2 , Tim S Maughan  3 , Christopher G Smith  4 , Jeremy P Cheadle  4 , David Fisher  5 , Richard Kaplan  5 , Philip Quirke  6 , Matthew T Seymour  7 , Susan D Richman  6 , Gerrit A Meijer  8 , Bauke Ylstra  8 , Danielle A M Heideman  8 , Anton F J de Haan  9 , Cornelis J A Punt  10 , Miriam Koopman  11
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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

Sabine Venderbosch et al. Clin Cancer Res. .

Abstract

Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) 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 BRAF(MT). BRAF(MT) 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 BRAF(MT) compared with BRAF wild-type (BRAF(WT)) 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 BRAF(MT) within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAF(WT) or BRAF(MT).

Conclusions: Prevalence of dMMR and BRAF(MT) 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 BRAF(MT) status.

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Figures

Figure 1
Figure 1. Progression-free (A) and overall survival (B) curves of all patients included in the pooled data set comparing patients with dMMR / BRAFMT tumors, dMMR / BRAFWT tumors, pMMR / BRAFMT tumors and pMMR / BRAFWT tumors
Figure 1
Figure 1. Progression-free (A) and overall survival (B) curves of all patients included in the pooled data set comparing patients with dMMR / BRAFMT tumors, dMMR / BRAFWT tumors, pMMR / BRAFMT tumors and pMMR / BRAFWT tumors
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