A Systematic Literature Review and Meta-Analysis Describing the Prevalence of KRAS, NRAS, and BRAF Gene Mutations in Metastatic Colorectal Cancer

Abstract

Background: Tumors of the metastatic colorectal cancer (mCRC) patients that are wildtype (WT) for KRAS or NRAS mutations respond more favorably to anti-epidermal growth factor receptor (EGFR) treatments. Treatment guidelines now recommend that all mCRC patients have WT KRAS and NRAS tumor status confirmed prior to initiating anti-EGFR therapy. Evidence also suggests that BRAF mutations may predict lack of response to anti-EGFR therapy. As such, there is now a need for comprehensive data on the prevalence of KRAS, NRAS, and BRAF mutations among patients with mCRC.Methods: A systematic literature review was conducted among studies that described the prevalence of KRAS, NRAS, and BRAF gene mutations in mCRC patients. Observational cohort studies and standard of care arm of randomized clinical trials were included. Random effects meta-analysis models were used to create summary prevalence estimates for each of the mutation types. Subgroup analyses were also conducted to identify potential sources of heterogeneity. Exploratory analyses of overall and progression-free survival by mutation status were also conducted. Results:This systematic review and meta-analysis included 275 studies comprising 77,104 mCRC patients. The summary prevalence estimate was 35.9% for KRAS mutations, 7.1% for BRAF mutations, and 4.1% for NRAS mutations. Female patients had significantly more KRAS and BRAF mutations than males, and significant variation by study location was observed for both KRAS and BRAF mutation prevalence. Overall survival was significantly decreased for patients with KRAS, BRAF, and NRAS mutations compared to those with WT tumors. Progression-free survival was also significantly decreased among patients with KRAS and BRAF mutations.Conclusions: KRAS, NRAS, and BRAF mutation statuses in patients with mCRC are important predictors of treatment success and may also have prognostic value. In this paper we present the first systematic and comprehensive literature review and meta-analysis of the prevalence of KRAS, BRAF, and NRAS mutations and demonstrate the prognostic impact of mutation status on survival.

Molecular characterization of colorectal cancer related peritoneal metastatic disease

“…1f and Supplementary Data 4). This is also considerably higher than recently reported mutation frequencies of KRAS in metastatic CRC (KRAS 35.9%, BRAF 7.1%, and NRAS 4.1%) 28 . In line with these observations, we detected enrichment of KRAS/BRAF mutations and increased KRAS signaling activity in primary stage II tumors (AMC-AJCCII-90) that will eventually recur as peritoneal metastatic disease (Supplementary Fig.…”

Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer

“…Patients with RAS mutated CRC are confronted with fewer treatment options and overall worse prognosis. Although the prognostic value of KRAS mutations remains somewhat controversial, many larger cohorts point into the direction of KRAS mutations as a poor prognostic factor [2][3][4][5]. The prognostic implications might even be mutation dependent.…”

Development of a disease conceptual model of patient experience with metastatic colorectal cancer: identification of the most salient symptoms and impacts.

“…The 5-year survival rate for CRC is 64%, but drops to 12% for mCRC, and further investigation is still required to develop effective approaches for medical intervention [2]. The implementation of new systemic treatment regimens for mCRC have signi cantly improved overall survival, with median survival for patients with mCRC having increased from 12 to 21 months in the decade from 2010 to 2020 [3].…”