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

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 current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Due to this relatively low incidence limited data concerning the role of MMR status in metastatic disease is available. In a pooled analysis involving 153 MSI CRCs in four phase III studies of first-line treatment of metastatic CRC (CAIRO, CAIRO2, COIN, FOCUS) the median PFS (HR 1.33; 95% CI 1.12-1.57, p = 0.001) and OS (HR 1.35; 95% CI 1.13-1.61, p = 0.001) were significantly worse in MSI CRCs compared to MSS (Venderbosch et al, 2014). The poorer survival of metastatic MSI CRC seems in part to be driven by the BRAF mutation (Goldstein et al, 2014).…”

S3-Leitlinie – Kolorektales Karzinom

“…BRAF-V600-Mutationen treten häufiger zusammen mit MSIals mit MSS-Status auf [1058]. Bei gleichzeitigem Auftreten von BRAF-V600-Mutationen und MSI handelt es sich um sporadisch auftretende Defekte der Mismatch-Reparatur (dMMR).…”

Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials

“…[3] The mechanism for the poor prognosis is poorly understood, and it is unclear at what point in the aCRC treatment pathway that Bmutant outcomes diverge from wildBtypes; whilst OS is uniformly poor, less impact is seen with PFS compared with wildBtypes. [4,5] It has been hypothesised that poor outcomes are secondary to intrinisc chemoresistance but there is a paucity of data describing the outcomes of Bmutant aCRC with chemotherapy alone, particularly beyond the firstBline. This is particularly important as B mutant patients have questionable benefit from antiBepidermal growth factor receptor (antiBEGFR) therapies [6] and Btargeted strategies have yet to make clinical impact in aCRC.…”

“…[7,8] Importantly previous publications have not performed careful multivariate analysis. This is critical as Bmutant aCRC is associated with clinicopathological features which are themselves negative prognostic factors, [9] including defective mismatch repair (dMMR) status [4,10] , right sided primary tumour location (PTL) [11] and a high incidence of peritoneal metastases. [12] The observed poor outcomes may instead be driven by such factors so it is essential to prospectively factor this into analyses of outcomes.…”