Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases

Abstract

BACKGROUND Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the incidence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM). METHODS KRAS and BRAF analysis was performed on 202 patients undergoing surgery for CRLM between 2003 and 2008. Tumor samples were analyzed for somatic mutations using sequencing analysis (KRAS, codon12/13, BRAF, V600E). The frequency of mutations was ascertained, and their impact on outcome was determined relative to other clinicopathologic factors. RESULTS KRAS gene mutations were detected in 58/202 patients (29%). In contrast, mutation in the BRAF gene was identified in very low frequency in this surgical cohort, found in only 4/202 (2%) patients. On multivariate analysis, KRAS mutation was associated with worse survival (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.21–3.26), as well as recurrence risk (HR, 1.68; 95% CI, 1.04–2.70). Although other clinicopathologic features, including tumor number, carcinoembryonic antigen, and primary stage were also associated with survival, KRAS status remained independently predictive of outcome. The low incidence of BRAF mutation limited assessment of its prognostic impact. CONCLUSION Whereas KRAS mutations were found in approximately one third of patients, BFAF mutations were found in only 2% of patients undergoing surgery for CRLM. KRAS status was an independent predictor of overall and recurrence-free survival. Molecular biomarkers such as KRAS may help to refine our prognostic assessment of patients undergoing surgical therapy for CRLM.

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

“…1). Three of these studies were retrospective series (Vauthey et al, 2013;Kemeny et al, 2014;Francesca Bergamo and Loupakis et al, 2014), while the others were prospective studies (Nash et al, 2010;Karagkounis et al, 2013;Stremitzer et al, 2012;Teng et al, 2012). In these 7 studies, sample sizes of the analyzed population ranged from 60 (Stremitzer et al, 2012) to 309 (Schirripa et al, 2015), while the percentage of KRAS mutated patients ranged from 14% (Stremitzer et al, 2012) to 37% (Teng et al, 2012).…”

“…In these 7 studies, sample sizes of the analyzed population ranged from 60 (Stremitzer et al, 2012) to 309 (Schirripa et al, 2015), while the percentage of KRAS mutated patients ranged from 14% (Stremitzer et al, 2012) to 37% (Teng et al, 2012). BRAF mutations were analysed in four of the seven included studies (Karagkounis et al, 2013;Stremitzer et al, 2012;Teng et al, 2012), and it was found in 2-4% of patients who underwent surgery for CLM. In nearly every trial, patients' characteristics were well balanced between the two arms.…”

“…Five studies reported HRs with 95% CI data for both RFS and OS (Karagkounis et al, 2013;Vauthey et al, 2013;Stremitzer et al, 2012;Kemeny et al, 2014), while two studies reported only HRs with 95% CI data for OS (Nash et al, 2010;Teng et al, 2012). Pooled analysis showed that KRAS mutations predicted a significant worse both RFS (HR: 1.53; 95% CI: 1.27-1.83) and OS (HR: 1.7; 95% CI: 1.38-2.10) in patients who underwent surgical resection of CLM (Figs.…”

“…The pooled HRs for both RFS and OS were calculated using fixed-effect model, because of non-significant heterogeneity between treatment effects (Q-test: P: 0.16; P: 0.11). Only three of the seven included studies analysed the OS of patients who underwent resection of CLM, according to BRAF mutation status (Karagkounis et al, 2013;Teng et al, 2012), while RFS data have not been reported in any of such studies. Pooled analysis showed that BRAF mutations predicted a significant worse OS (HR: 3.07; 95% CI: 1.67-5.66) in this subgroup of CRC patients (Fig.…”

“…The majority of such studies have shown that both KRAS and BRAF, respectively detected in about 30% and 3% of CLM, are associated with worse survival outcomes of patients undergoing liver resection (Nash et al, 2010;Karagkounis et al, 2013;Vauthey et al, 2013;Stremitzer et al, 2012), while some other studies have not found a significant association (Kemeny et al, 2014;Teng et al, 2012;Schirripa et al, 2015). The aim of this meta-analysis is to combine and analyze simultaneously all the studies reporting the survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status, in order to provide a more precise estimation of the prognostic value of both KRAS and BRAF, in patients undergoing surgical therapy for CLM.…”