Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer.
Details
Serval ID
serval:BIB_402938216678
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer.
Journal
Clinical Cancer Research
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
17
Number
10
Pages
3469-3477
Language
english
Notes
Publication types: Evaluation Studies ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
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.
Keywords
Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal/adverse effects, Antibodies, Monoclonal/therapeutic use, Antibodies, Monoclonal, Humanized, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, Biomarkers, Pharmacological/analysis, Biomarkers, Pharmacological/metabolism, Carcinoma/drug therapy, Carcinoma/genetics, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Combined Modality Therapy, Disease Progression, Female, Gene Expression Regulation, Neoplastic/drug effects, Gene Expression Regulation, Neoplastic/radiation effects, Humans, Male, Middle Aged, Neoadjuvant Therapy, Rectal Neoplasms/drug therapy, Rectal Neoplasms/genetics, Retrospective Studies, Tumor Markers, Biological/analysis, Tumor Markers, Biological/genetics
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2015 14:05
Last modification date
20/08/2019 14:37