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

Int J Cancer. 2013 Oct 15;133(8):1914-25. doi: 10.1002/ijc.28153. Epub 2013 Jul 13.


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 worseoutcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs [corrected]. 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.

Keywords: KRAS; biomarker; colorectal cancer; meta-analysis; monoclonal antibody.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / therapeutic use
  • Biomarkers, Tumor
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality*
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / immunology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / genetics*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Treatment Outcome
  • Young Adult
  • ras Proteins / genetics*
  • ras Proteins / metabolism


  • Antibodies, Monoclonal
  • Biomarkers, Tumor
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins