Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab

• Published in: Journal of clinical oncology Vol. 25; no. 22; pp. 3230 - 3237
• Main Authors: KHAMBATA-FORD, Shirin, GARRETT, Christopher R, TAN, Benjamin R, KRISHNAMURTHI, Smitha S, BURRIS, Howard A, POPLIN, Elizabeth A, HIDALGO, Manuel, BASELGA, Jose, CLARK, Edwin A, MAURO, David J, MEROPOL, Neal, BASIK, Mark, HARBISON, Christopher T, SHUJIAN WU, WONG, Tai W, XIN HUANG, TAKIMOTO, Chris H, GODWIN, Andrew K
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.08.2007; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Aged, 80 and over; Amphiregulin; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - analysis; Cetuximab; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; EGF Family of Proteins; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Epiregulin; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Genes, ras; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Male; Medical sciences; Middle Aged; Mutation; Neoplasm Metastasis; Predictive Value of Tests; Proportional Hazards Models; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Rate; Treatment Outcome; Tumors; Antineoplastic agent; Human; Rectal disease; Colorectal cancer; Monoclonal antibody; Malignant tumor; Metastasis; Epidermal growth factor receptor; Colonic disease; K ras Gene; Cancerology; Treatment; C-Onc gene; Digestive diseases; Intestinal disease; Advanced stage; Mutation; Cetuximab; Predictive factor; Onc gene; Ras gene; Protooncogene
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2006.10.5437

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. 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. 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). 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.