Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.

Abstract

PURPOSE:

The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.

PATIENTS AND METHODS:

One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.

RESULTS:

Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).

CONCLUSION:

Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

• Authors: Shirin Khambata-Ford, Christopher R Garrett, Neal J Meropol, Mark Basik, Christopher T Harbison, Shujian Wu, Tai W Wong, Xin Huang, Chris H Takimoto, Andrew K Godwin, Benjamin R Tan, Smitha S Krishnamurthi, Howard A Burris 3rd, Elizabeth A Poplin, Manuel Hidalgo, Jose Baselga, Edwin A Clark, David J Mauro
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 25 Issue 22 Pg. 3230-7 (Aug 01 2007) ISSN: 1527-7755 [Electronic] United States
• PMID: 17664471 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• AREG protein, human
• Amphiregulin
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Biomarkers, Tumor
• EGF Family of Proteins
• EREG protein, human
• Epiregulin
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Epidermal Growth Factor
• ErbB Receptors
• Cetuximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Amphiregulin
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (analysis)
• Cetuximab
• Colorectal Neoplasms (drug therapy, genetics)
• EGF Family of Proteins
• Enzyme-Linked Immunosorbent Assay
• Epidermal Growth Factor (genetics, metabolism)
• Epiregulin
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Female
• Gene Expression Profiling
• Genes, ras
• Glycoproteins (genetics, metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Predictive Value of Tests
• Proportional Hazards Models
• Survival Rate
• Treatment Outcome