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Title: Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab
Authors: Jacobs, Bart
De Roock, Wendy
Piessevaux, Hubert
Van Oirbeek, Robin
Biesmans, Bart
De Schutter, Jef
Fieuws, Steffen
Vandesompele, Jo
Peeters, Marc
Van Laethem, Jean-Luc
Humblet, Yves
Penault-Llorca, Frederique
De Hertogh, Gert
Laurent-Puig, Pierre
Van Cutsem, Eric
Tejpar, Sabine
Issue Date: 2009
Citation: JOURNAL OF CLINICAL ONCOLOGY, 27(30). p. 5068-5074
Abstract: 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 tau index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; C tau index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; C tau index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; C tau 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.
Notes: [Tejpar, Sabine] Katholieke Univ Leuven, Digest Oncol Unit, Dept Pathol, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Ctr Human Genet, B-3000 Louvain, Belgium. Katholieke Univ Leuven, Interuniv Inst Biostat & Stat Bioinformat, B-3000 Louvain, Belgium. Univ Hasselt, Hasselt, Belgium. Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. Ghent Univ Hosp, Digest Oncol Unit, B-9000 Ghent, Belgium. Univ Catholique Louvain, Clin Univ St Luc, Serv Gastroenterol, Louvain, Belgium. Univ Catholique Louvain, Clin Univ St Luc, Ctr Canc, Louvain, Belgium. Univ Libre Bruxelles, Dept Gastroenterol, Gastrointestinal Canc Unit, Erasme Univ Hosp, Brussels, Belgium. Ctr Jean Perrin, Dept Pathol, Clermont Ferrand, France. Univ Paris 05, Assistance Publ Hop Paris, Paris, France. Inst Natl Sante & Rech Med, Paris, France.
URI: http://hdl.handle.net/1942/10001
DOI: 10.1200/JCO.2008.21.3744
ISI #: 000270875100024
ISSN: 0732-183X
Category: A1
Type: Journal Contribution
Validation: ecoom, 2010
Appears in Collections: Research publications

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