Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer

Abstract

Background:Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.Methods:We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.Results:Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67–1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70–0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61–1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50–0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07).Interpretation:This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

Eastern Canadian Colorectal Cancer Consensus Conference 2017

“…However, the test of interaction (p = 0.43) was not statistically significant, highlighting the possibility that the observed differences in the effect of anti-egfr mAbs on os according to the BRAF mutation status might be attributable to chance alone. With respect to the pfs benefit with anti-egfr mAbs, the hr was 0.86 (95% ci: 0.61 to 1.21) for RAS wt, BRAF-mutant tumours and 0.62 (95% ci: 0.50 to 0.77) for RAS wt, BRAF wt tumours (test of interaction, p = 0.07) 87 .…”

“…Advances in molecular biology since the late 1990s have helped to identify and understand the mechanism of colorectal carcinogenesis. In metastatic crc, egfr and the downstream mapk pathways play a major role in disease progression and have led to the development of multiple targeted therapies 87 . Colorectal cancer can be classified according to molecular markers.…”

“…Overall, compared with control regimens, the addition of cetuximab or panitumumab treatment in the BRAF-mutant subgroup did not significantly improve pfs (hr: 0.88; 95% ci: 0.67 to 1.14; p = 0.33), os (hr: 0.91; 95% ci: 0.62 to 1.34; p = 0.63), or orr (relative risk: 1.31; 95% ci: 0.83 to 2.08; p = 0.25) 94 . Another meta-analysis by Rowland et al 87 included seven randomized controlled trials that met the inclusion criteria for assessment of os and eight trials that met the inclusion criteria for assessment of pfs. For RAS wt, BRAF-mutant tumours, the hr for os benefit with anti-egfr mAbs was 0.97 (95% ci: 0.67 to 1.41); the hr for RAS wt, BRAF wt tumours was 0.81 (95% ci: 0.70 to 0.95).…”

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

“…[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.…”

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology

“…Nor was there sufficient evidence to identify a statistically significant benefit to this treatment. 55 A second meta-analysis showed that EGFR monoclonal antibody treatment in patients whose tumors contain a BRAF p.V600 mutation was not associated with significant OS (P ¼ .43), although there was a trend for better PFS (P ¼ .07).…”