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

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

Author information

1
Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide michael.sorich@flinders.edu.au.
2
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide.
3
Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide.
4
Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.

Abstract

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

PMID:
25115304
DOI:
10.1093/annonc/mdu378
[Indexed for MEDLINE]

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