Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies.
Venderbosch S1, Nagtegaal ID2, Maughan TS3, Smith CG4, Cheadle JP4, Fisher D5, Kaplan R6, Quirke P7, Seymour MT8, Richman S9, Meijer GA10, Ylstra B11,Heideman DA12, de Haan AF13, Punt CJ14, Koopman M15.
Clin Cancer Res. 2014 Aug 19. pii: clincanres.0332.2014. [Epub ahead of print]
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 3063 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 to 197 (6.8%) of patients with proficient MMR (pMMR) tumors (p<0.001). In the pooled data set, median PFS and OS were significantly worse for patients with dMMR compared to pMMR tumors (HR 1.33, 95% CI 1.12-1.57 and HR 1.35, 95% CI 1.13-1.61, respectively), and for patients with BRAFMT compared to 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 mCRC patients is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by BRAFMT status.
Copyright © 2014, American Association for Cancer Research.