Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer.

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.

• Authors: Peter P Grimminger, Peter Danenberg, Kathrin Dellas, Dirk Arnold, Claus Rödel, Jean-Pascal Machiels, Karin Haustermans, Annelies Debucquoy, Vaneja Velenik, Christine Sempoux, Matej Bracko, Arnulf H Hölscher, Robert Semrau, Dongyun Yang, Kathleen Danenberg, Heinz-Josef Lenz, Daniel Vallböhmer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 10 Pg. 3469-77 (May 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21558395 (Publication Type: Evaluation Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Biomarkers, Pharmacological
• Biomarkers, Tumor
• Cetuximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (adverse effects, therapeutic use)
• Biomarkers, Pharmacological (analysis, metabolism)
• Biomarkers, Tumor (analysis, genetics)
• Carcinoma (drug therapy, genetics, pathology, radiotherapy)
• Cetuximab
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Combined Modality Therapy
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy
• Rectal Neoplasms (drug therapy, genetics, pathology, radiotherapy)
• Retrospective Studies