Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer.

Abstract

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-alpha 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.

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.

• Authors: Annelies Debucquoy, Karin Haustermans, Anneleen Daemen, Selda Aydin, Louis Libbrecht, Olivier Gevaert, Bart De Moor, Sabine Tejpar, William H McBride, Freddy Penninckx, Pierre Scalliet, Christopher Stroh, Soetkin Vlassak, Christine Sempoux, Jean-Pascal Machiels
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 17 Pg. 2751-7 (Jun 10 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19332731 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Biomarkers
• Deoxycytidine
• Capecitabine
• Cetuximab
• Fluorouracil

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols
• Biomarkers (analysis)
• Capecitabine
• Cetuximab
• Combined Modality Therapy
• Deoxycytidine (analogs & derivatives, therapeutic use)
• Drug Resistance, Neoplasm
• Fluorouracil (analogs & derivatives, therapeutic use)
• Gene Expression (drug effects, radiation effects)
• Humans
• Neoplasm Staging
• Prognosis
• Radiotherapy Dosage
• Rectal Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Treatment Outcome