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Originally published as JCO Early Release 10.1200/JCO.2008.18.5033 on March 30 2009 © 2009 American Society of Clinical Oncology.
Molecular Response to Cetuximab and Efficacy of Preoperative Cetuximab-Based Chemoradiation in Rectal CancerDepartments of Radiation Oncology and Pathology, Leuven Cancer Institute, University Hospitals Leuven; Department of Electrical Engineering (ESAT-SCD), Katholieke Universiteit Leuven; Digestive Oncology Unit, Department of Internal Medicine, and Department of Abdominal Surgery, University Hospital Gasthuisberg, Leuven; Departments of Pathology, Radiation Oncology, and Medical Oncology, Clinique des Pathologies Tumorales du Colon et du Rectum, Centre du Cancer, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels; Merck nv/sa, Overijse, Belgium; Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; and Merck Serono, Merck KGaA, Darmstadt, Germany. Corresponding author: Annelies Debucquoy, MSc, Lab of Experimental Radiotherapy, Department of Radiation Oncology, CDG Building, Box 815, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; e-mail: annelies.debucquoy{at}med.kuleuven.be. Purpose To characterize the molecular pathways activated or inhibited by cetuximab when combined with chemoradiotherapy (CRT) in rectal cancer and to identify molecular profiles and biomarkers that might improve patient selection for such treatments. Patients and Methods Forty-one patients with rectal cancer (T3-4 and/or N+) received preoperative radiotherapy (1.8 Gy, 5 days/wk, 45 Gy) in combination with capecitabine and cetuximab (400 mg/m2 as initial dose 1 week before CRT followed by 250 mg/m2 /wk for 5 weeks). Biopsies and plasma samples were taken before treatment, after cetuximab but before CRT, and at the time of surgery. Proteomics and microarrays were used to monitor the molecular response to cetuximab and to identify profiles and biomarkers to predict treatment efficacy.
Results Cetuximab on its own downregulated genes involved in proliferation and invasion and upregulated inflammatory gene expression, with 16 genes being significantly influenced in microarray analysis. The decrease in proliferation was confirmed by immunohistochemistry for Ki67 (P = .01) and was accompanied by an increase in transforming growth factor- Conclusion Our study showed that a single dose of cetuximab has a significant impact on the expression of genes involved in tumor proliferation and inflammation. We identified potential biomarkers that might predict response to cetuximab-based CRT. Supported by Merck Serono, Varian Biosynergy, Belgian Foundation against Cancer. K. Haustermans is supported by a fundamental clinical mandate of the Research Foundation Flanders (FWO). A. Debucquoy was supported by an "Emmanuel van der Schueren" grant of the Flemish League against Cancer. Presented in part at the 13th International Congress of Radiation Research, July 8-12, 2007, San Francisco, CA; at the 10th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, May 12-14, 2007, Wolfsberg, Switzerland; and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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in plasma samples (P < .001). Disease-free survival (DFS) was better in patients if epidermal growth factor receptor expression was upregulated in the tumor after the initial cetuximab dose (P = .02) and when fibro-inflammatory changes were present in the surgical specimen (P = .03). Microarray and proteomic profiles were predictive of DFS. 
