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A Systematic Literature Review and Meta-Analysis Describing the Prevalence of KRAS, NRAS, and BRAF Gene Mutations in
Elizabeth Levin-Sparenberg1, Lauren C Bylsma1, Kimberly Lowe2
1Epidstat Institute, Ann Arbor, MI, USA.
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.
Insights
Metastatic colorectal cancer (mCRC) patients with KRAS, NRAS, or BRAF mutations have poorer survival outcomes. Understanding the prevalence of these mutations is crucial for guiding anti-EGFR therapy selection in mCRC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic colorectal cancer (mCRC) treatment response is influenced by specific gene mutations.
- Wildtype (WT) status for KRAS and NRAS mutations predicts better outcomes with anti-EGFR therapy.
- BRAF mutations may also indicate a lack of response to anti-EGFR treatments, necessitating comprehensive prevalence data.
Purpose of the Study:
- To systematically review and meta-analyze the prevalence of KRAS, NRAS, and BRAF mutations in mCRC patients.
- To assess the prognostic impact of these mutations on patient survival.
- To provide a comprehensive overview of mutation frequencies to inform clinical guidelines.
Main Methods:
- Systematic literature review of observational studies and RCTs involving mCRC patients.
- Random effects meta-analysis to estimate summary prevalence for KRAS, NRAS, and BRAF mutations.
- Subgroup and exploratory analyses to investigate heterogeneity and survival outcomes by mutation status.
Main Results:
- Included 275 studies with 77,104 mCRC patients.
- Summary prevalence: KRAS mutations (35.9%), BRAF mutations (7.1%), NRAS mutations (4.1%).
- Mutations were associated with significantly decreased overall and progression-free survival compared to WT tumors.
Conclusions:
- KRAS, NRAS, and BRAF mutation status are key predictors of treatment success in mCRC.
- These mutations hold significant prognostic value, impacting patient survival.
- This meta-analysis provides the most comprehensive data to date on mutation prevalence and prognostic impact in mCRC.
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