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Title: Biomarkers for Cetuximab-Based Neoadjuvant Radiochemotherapy in Locally Advanced Rectal Cancer
Authors: Grimminger, Peter P × Danenberg, Peter Dellas, Kathrin Arnold, Dirk Rödel, Claus Machiels, Jean-Pascal Haustermans, Karin Debucquoy, Annelies Velenik, Vaneja Sempoux, Christine Bracko, Matej Hölscher, Arnulf H Semrau, Robert Yang, Dongyun Danenberg, Kathleen Lenz, Heinz-Josef Vallböhmer, Daniel #
Issue Date: 15-May-2011
Publisher: Association for Cancer Research
Series Title: Clinical Cancer Research vol:17 issue:10 pages:3469-3477
Abstract: PURPOSE: Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF. EXPERIMENTAL DESIGN: This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed. RESULTS: A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P < 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P = 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P = 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P = 0.012; P = 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P = 0.007). BRAF V600E mutations were not detected in any of the patients. CONCLUSION: This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximab-based chemoradiation in locally advanced rectal cancer. Clin Cancer Res; 17(10); 1-9. ©2011 AACR.
Publication status: published
KU Leuven publication type: IT
Appears in Collections: Laboratory of Experimental Radiotherapy
× corresponding author
# (joint) last author
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