Abstract | BACKGROUND: MATERIALS AND METHODS:
Formalin-fixed paraffin-embedded colorectal cancer tissue of the primary tumour was obtained from 559 mCRC patients treated with chemotherapy and bevacizumab with or without cetuximab (phase III CAIRO2 study). DNA was isolated for mutation analysis of BRAF (V600E), KRAS ( codon 12 and 13) and PIK3CA (exon 9 and 20). Tissue microarray's (TMA's) were constructed for the assessment of EGFR and HER2 gene copy number (GCN), and EGFR and PTEN protein expression. The results of these markers, individually or in combination, were correlated with progression-free survival (PFS) and overall survival (OS) in the subgroup of patients with a KRAS wild type tumour treated in the cetuximab-arm. KRAS wild type patients treated without cetuximab were used as a control group. RESULTS: A total of 208 tumours (39.4%) contained a KRAS mutation, 8.7% a BRAF mutation and 9.9% a PIK3CA mutation. Loss of PTEN expression and the presence EGFR protein expression were observed in 42.0% and 61.7% of the samples, respectively. An increased EGFR GCN was observed in 15.3% of the samples, and 11.5% of the evaluable samples contained an increased HER2 GCN. In KRAS wild type patients treated with cetuximab a BRAF mutation was significantly and independently associated with PFS and OS. In patients treated without cetuximab the PFS and OS were also associated with the BRAF genotype. No prognostic or predictive value was observed for any of the other markers when tested individually or in combination. CONCLUSIONS: BRAF genotype is correlated with PFS and OS in KRAS wild type mCRC patients, which is independent of cetuximab treatment. PIK3CA mutation, loss of PTEN expression, EGFR GCN and HER2 GCN have no predictive value for response to treatment with cetuximab, neither individually nor in combination with other markers.
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Authors | Jolien Tol, Jeroen R Dijkstra, Marjolein Klomp, Steven Teerenstra, Martin Dommerholt, M Elisa Vink-Börger, Patricia H van Cleef, J Han van Krieken, Cornelis J A Punt, Iris D Nagtegaal |
Journal | European journal of cancer (Oxford, England : 1990)
(Eur J Cancer)
Vol. 46
Issue 11
Pg. 1997-2009
(Jul 2010)
ISSN: 1879-0852 [Electronic] England |
PMID | 20413299
(Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 2010 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Biomarkers, Tumor
- KRAS protein, human
- Neoplasm Proteins
- Proto-Oncogene Proteins
- Phosphatidylinositol 3-Kinases
- Class I Phosphatidylinositol 3-Kinases
- PIK3CA protein, human
- ErbB Receptors
- BRAF protein, human
- Proto-Oncogene Proteins B-raf
- PTEN Phosphohydrolase
- PTEN protein, human
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
- Cetuximab
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Topics |
- Antibodies, Monoclonal
(therapeutic use)
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
(therapeutic use)
- Biomarkers, Tumor
(genetics, metabolism)
- Cetuximab
- Class I Phosphatidylinositol 3-Kinases
- Colorectal Neoplasms
(drug therapy, genetics, metabolism)
- ErbB Receptors
(metabolism)
- Female
- Genes, Neoplasm
(genetics)
- Genes, erbB-2
(genetics)
- Genes, ras
(genetics)
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Male
- Middle Aged
- Mutation
(genetics)
- Neoplasm Proteins
(metabolism)
- PTEN Phosphohydrolase
(metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Proto-Oncogene Proteins
(metabolism)
- Proto-Oncogene Proteins B-raf
(metabolism)
- Proto-Oncogene Proteins p21(ras)
- Treatment Outcome
- ras Proteins
(metabolism)
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