Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab

• Published in: European journal of cancer (1990) Vol. 46; no. 11; pp. 1997 - 2009
• Main Authors: Tol, Jolien, Dijkstra, Jeroen R, Klomp, Marjolein, Teerenstra, Steven, Dommerholt, Martin, Vink-Börger, M. Elisa, van Cleef, Patricia H, van Krieken, J. Han, Punt, Cornelis J.A, Nagtegaal, Iris D
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.07.2010; Elsevier
• Subjects: Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; BRAF; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Female; Genes, erbB-2 - genetics; Genes, Neoplasm - genetics; Genes, ras - genetics; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Medical sciences; Metastatic colorectal cancer; Middle Aged; Mutation - genetics; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; PI3K pathway; Predictive markers; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase - metabolism; ras Proteins - metabolism; RAS/MAPK pathway; Receptor, Epidermal Growth Factor - metabolism; Treatment Outcome; Tumors; PI3K pathway; Predictive markers; BRAF; RAS/MAPK pathway; Cetuximab; Metastatic colorectal cancer; Antineoplastic agent; Rectal disease; Prognosis; Colorectal cancer; Biological marker; Monoclonal antibody; Metastasis; Epidermal growth factor receptor; BRAF Gene; Cancerology; Intestinal disease; Advanced stage; Protooncogene; Human; Enzyme; Transferases; Mitogen-activated protein kinase; Malignant tumor; 1-Phosphatidylinositol 3-kinase; Colonic disease; Treatment; C-Onc gene; Digestive diseases; Predictive factor; Ras gene; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2010.03.036

Abstract Background Anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) treatment are only effective in patients with KRAS wild type tumours. Here we assess the predictive value of other potential relevant markers involved in the epidermal growth factor receptor (EGFR) signalling pathways for response to cetuximab-based treatment. 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.