The Prognostic and Predictive Impact of BRAF Mutations in Deficient Mismatch Repair/Microsatellite Instability-High Colorectal Cancer: Systematic Review/Meta-Analysis

Abstract

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I–IV patients (hazard ratio: 1.57; 95% CI: 1.23–1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48–2.25). Conclusion:BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Lay abstract

Patients with colorectal cancer who have mutations in the BRAF gene fare worse compared with those without the mutation, whereas those who have a feature called microsatellite instability-high tend to live longer compared with those who do not have this feature. However, it is unclear whether the presence of BRAF gene mutation changes the course of the disease or response to novel immunotherapy treatment in patients with microsatellite instability-high colorectal cancer. The authors found that patients without the BRAF mutation live longer than their counterparts with the mutation. The two groups did not respond differently to immunotherapy. Therefore, BRAF mutations are important in dictating the disease course in patients with microsatellite instability-high colorectal cancer.

Keywords:

• BRAF
• immunotherapy
• microsatellite instability
• mismatch repair deficiency
• prognosis

Supplementary data

To view the supplementary data that accompany this paper, please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fon-2021-0552

Author contributions

Conceptualization: R Park and A Saeed. Methodology: R Park and A Saeed. Software: R Park. Validation: R Park, L Lopes, S Lee, I Riano and A Saeed. Formal analysis: R Park, L Lopes, S Lee and I Riano. Investigation: R Park, L Lopes, S Lee and I Riano. Data curation: R Park, L Lopes, S Lee and I Riano. Original draft preparation: R Park, L Lopes, S Lee and I Riano. Review and editing: R Park, L Lopes, S Lee, I Riano and A Saeed. Visualization: R Park. Supervision: A Saeed. Project administration: A Saeed. All authors have read and agreed to the published version of the manuscript.

Financial & competing interests disclosure

A Saeed has received institutional research grants from AstraZeneca, Exelixis, Merck, Bristol Myers Squibb, Clovis, Celgene and KAHR Medical and advisory board fees from Merck, AstraZeneca, Bristol Myers Squibb and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

A Saeed has received institutional research grants from AstraZeneca, Exelixis, Merck, Bristol Myers Squibb, Clovis, Celgene and KAHR Medical and advisory board fees from Merck, AstraZeneca, Bristol Myers Squibb and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed