Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer

• Published in: British journal of cancer Vol. 110; no. 3; pp. 648 - 655
• Main Authors: Jonker, D J, Karapetis, C S, Harbison, C, O'Callaghan, C J, Tu, D, Simes, R J, Malone, D P, Langer, C, Tebbutt, N, Price, T J, Shapiro, J, Siu, L L, Wong, R P W, Bjarnason, G, Moore, M J, Zalcberg, J R, Khambata-Ford, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2014; Nature Publishing Group
• Subjects: 692/53; 692/699/67/1059/2325; 692/699/67/1504/1885; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cetuximab; Clinical trials; Clinical Trials, Phase III as Topic; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease-Free Survival; Drug Resistance; Epidemiology; Epidermal growth factor; Epidermal Growth Factor - biosynthesis; Epidermal Growth Factor - genetics; Epiregulin; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation, Neoplastic; Hospitals; Humans; Ligands; Male; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Neoplasm Staging; Oncology; ras Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Translational Therapeutics; Tumors; Australia; Canada; United States > US; amphiregulin; cetuximab; biomarker; epiregulin; colorectal; EGFR; Antineoplastic agent; Rectal disease; Colorectal cancer; Biological marker; Monoclonal antibody; Epidermal growth factor receptor; K ras Gene; Cancerology; K-ras; Intestinal disease; Advanced stage; Colon; Cetuximab; Protooncogene; Digestive system; Gut; Malignant tumor; Gene expression; EREG; Colonic disease; Immunomodulator; Treatment; C-Onc gene; Rectum; Digestive diseases; Onc gene; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.753

Background: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy–refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin ( EREG ) gene expression may further predict cetuximab benefit. Methods: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment–biomarker interaction. Results: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status (‘co-biomarker’)-positive group ( n =139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P <0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P <0.001) for cetuximab vs BSC, respectively. In the rest ( n =246, 64%), PFS (HR 0.82; P =0.12) and OS (HR 0.90; P =0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P =0.007) and PFS (HR 0.49; P =0.001) in the co-biomarker-positive group. Conclusion: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.