Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A systematic review with meta-analysis

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs). However, many patients with KRAS wild-type tumors still do not respond to the treatment. We conducted a systematic review with meta-analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild-type mCRC treated with anti-EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression-free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random-effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR=2.59, 95% CI 1.67-4.03; HR=2.52, 95% CI 1.33-4.78 and HR=1.75, 95% CI 1.19-2.56, respectively), shorter OS (HR=2.74, 95% CI 1.79-4.19; HR=3.29, 95% CI 1.60-6.75 and HR=1.85, 95% CI 1.30-2.64, respectively) and lower ORR (RD=-36%, 95% CI -44 to -28%; RD=-38%, 95% CI -51 to -24% and RD=-41%, 95% CI -68 to -14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of better outcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs. However, the quality of included studies varied, and some of the meta-analyses were limited by significant between-study heterogeneity. In the future, well-designed large randomized controlled trials conducted in KRAS wild-type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers. What's new? Metastatic colorectal cancer (mCRC) is associated with a particularly poor prognosis. Monoclonal antibodies against EGFR are effective, but only for a small percentage of mCRC patients. KRAS mutations are a major predictive biomarker for resistance to anti-EGFR therapy; however, many patients with wild-type KRAS also fail to respond. In order to identify other potential biomarkers, the authors conducted a meta-analysis of previous studies, and found that BRAF mutation, PIK3CA exon 20 mutation, and PTEN loss were consistently associated with a poor response. These data may allow further selection of KRAS wild-type mCRC patients who may benefit from anti-EGFR treatment.