Originally published as JCO Early Release 10.1200/JCO.2008.21.3744 on September 8 2009

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Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

From the Department of Pathology, Digestive Oncology Unit, and Center for Human Genetics, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven; Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Katholieke Universtiteit Leuven, Leuven, and Universiteit Hasselt, Hasselt; Center for Medical Genetics and Digestive Oncology Unit, University Hospital Ghent, Ghent; Service de Gastro-entérologie and Centre du Cancer, Cliniques Universitaires Saint-Luc, Université catholique de Louvain; Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; Department of Pathology, Centre Jean Perrin, Clermont-Ferrand; and Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, and L'Institut National de la Santé et de la Recherche Médicale, Paris, France.

Corresponding author: Sabine Tejpar, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; e-mail: Sabine.Tejpar{at}uz.kuleuven.ac.be.

Purpose To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands' expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan.

Patients and Methods Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting.

Results In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [C index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; C index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; C index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; C index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation.

Conclusion Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

Supported by a grant from the Belgian Foundation Against Cancer; by a PhD grant from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen; B.J. and W.D.R.); by the Institut National du Cancer PL-019 (P.L.-P.); and by the Fund for Scientific Research Flanders (S.T., E.V.C., and M.P.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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