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

By S. Venderbosch, I. Nagtegaal, T. Maughan, Christopher G. Smith, J. Cheadle, D. Fisher, R. Kaplan, P. Quirke, M. Seymour, S. Richman and 6 more. Clinical Cancer Research, 2014

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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.

Subfields: Epidemiology, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/135c76704af4b224bdda4a72b9646744e30dd5c4

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Citations in the corpus

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. (2016, methodology): “Oliveira C, Velho S, Moutinho C et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression.”
Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. (2018, neutral): “1 (8-20) 12 (40) 3 (50) Not reached (2-93) Not reached (2-48) 11 (37) 4 (67) GI 27 (23) 4 (3) 9.”
FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors (2019, background): “The rate of MSI appears lower in the metastatic setting, with approximately 5% of colorectal cancers being MSIH (7, 10).”
Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164 (2019, neutral): “Hyperthyroidism 3 (5) 0 (0) 7 (11) 0 (0)”