Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab.

Abstract

PURPOSE:

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles.

PATIENTS AND METHODS:

Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis.

RESULTS:

No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.

CONCLUSION:

In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.

• Authors: Marc Peeters, Jean-Yves Douillard, Eric Van Cutsem, Salvatore Siena, Kathy Zhang, Richard Williams, Jeffrey Wiezorek
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 31 Issue 6 Pg. 759-65 (Feb 20 2013) ISSN: 1527-7755 [Electronic] United States
• PMID: 23182985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Biomarkers, Tumor
• Codon
• KRAS protein, human
• Organoplatinum Compounds
• Proto-Oncogene Proteins
• Oxaliplatin
• Panitumumab
• Irinotecan
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Alleles
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Camptothecin (administration & dosage, analogs & derivatives)
• Codon (genetics)
• Colorectal Neoplasms (drug therapy, genetics)
• Drug Resistance, Neoplasm (genetics)
• Fluorouracil (administration & dosage)
• Gene Frequency
• Humans
• Irinotecan
• Leucovorin (administration & dosage)
• Mutation
• Neoplasm Metastasis
• Organoplatinum Compounds (administration & dosage)
• Outcome Assessment, Health Care
• Oxaliplatin
• Panitumumab
• Prognosis
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Randomized Controlled Trials as Topic
• Retrospective Studies
• Survival Analysis
• ras Proteins (genetics)