Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials

Ann Oncol. 2015 Jan;26(1):13-21. doi: 10.1093/annonc/mdu378. Epub 2014 Aug 12.


Background: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.

Methods: Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.

Results: Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).

Conclusion: Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.

Keywords: RAS mutation; cetuximab; meta-analysis; panitumumab; pharmacogenomics; predictive biomarker.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / therapeutic use*
  • Cetuximab
  • Colorectal Neoplasms / drug therapy*
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / immunology
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Membrane Proteins / genetics*
  • Panitumumab
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins / genetics*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • KRAS protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Panitumumab
  • ErbB Receptors
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab