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Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a

M J Sorich1, M D Wiese2, A Rowland1

  • 1Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|August 14, 2014
PubMed
Abstract

Insights

New RAS mutations in metastatic colorectal cancer (mCRC) predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy. Patients with these mutations show no significant survival benefit from anti-EGFR mAb treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Clinical Trials

Background:

  • Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) improve survival in metastatic colorectal cancer (mCRC) with Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors.
  • Emerging evidence suggests that additional RAS mutations (KRAS exons 3-4, NRAS exons 2-4) may also indicate resistance to anti-EGFR therapy.

Purpose of the Study:

  • To systematically review and meta-analyze randomized controlled trials (RCTs) evaluating anti-EGFR mAbs.
  • To assess the predictive value of new RAS mutations for treatment response to anti-EGFR mAbs in mCRC.
  • To compare outcomes for tumors with new RAS mutations versus those without RAS mutations or with KRAS exon 2 mutations.

Main Methods:

  • Systematic review and meta-analysis of nine RCTs involving 5948 participants.
  • Included trials assessed tumors for both KRAS exon 2 and new RAS mutations.
  • Compared progression-free survival (PFS) and overall survival (OS) based on RAS mutation status.

Main Results:

  • Approximately 20% of KRAS exon 2 wild-type tumors had new RAS mutations.
  • Tumors without any RAS mutations showed significantly superior PFS (P < 0.001) and OS (P = 0.008) with anti-EGFR mAbs compared to tumors with any RAS mutation.
  • No significant PFS or OS benefit was observed with anti-EGFR mAbs in tumors harboring any RAS mutation (P > 0.05).
  • Results were consistent across different anti-EGFR agents, therapy lines, and chemotherapy partners.

Conclusions:

  • Tumors with new RAS mutations are unlikely to benefit from anti-EGFR mAb therapy in mCRC.
  • RAS mutation status beyond KRAS exon 2 is crucial for predicting response to anti-EGFR therapies in mCRC.
Keywords:
RAS mutationcetuximabmeta-analysispanitumumabpharmacogenomicspredictive biomarker

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