Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer

The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFRi) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFRi group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFRi tumours (HR, 1.53; 95% CI, 1.04–2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.

[1]  R. Henriksson,et al.  ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases. , 2009, Anticancer research.

[2]  M. Molaei,et al.  Human epidermal growth factor receptor-2 family in colorectal adenocarcinoma: correlation with survival and clinicopathological findings , 2009, European journal of gastroenterology & hepatology.

[3]  Simone Brabletz,et al.  E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer , 2009, Cancer and Metastasis Reviews.

[4]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[5]  A. Nonomura,et al.  Prognostic value of immunohistochemical analysis of tumor budding in colorectal carcinoma. , 2008, Anticancer research.

[6]  A. Lièvre,et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  H. S. Abd El All,et al.  Epidermal growth factor receptor in colorectal carcinoma: correlation with clinico‐pathological prognostic factors , 2007, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[8]  H. Mitomi,et al.  Tumour budding at invasive margins and outcome in colorectal cancer , 2007, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[9]  S. Thomson,et al.  Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions , 2008, Clinical & Experimental Metastasis.

[10]  S. Kakar,et al.  Comparison of the Dako EGFR pharmDx Kit and Zymed EGFR Antibody for Assessment of EGFR Status in Colorectal Adenocarcinoma , 2007, Applied immunohistochemistry & molecular morphology : AIMM.

[11]  R. Palmqvist,et al.  High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer , 2007, Clinical Cancer Research.

[12]  J. Haley,et al.  Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition , 2007, Molecular Cancer Therapeutics.

[13]  G. Christofori.  New signals from the invasive front , 2006, Nature.

[14]  H. Beug,et al.  Molecular requirements for epithelial-mesenchymal transition during tumor progression. , 2005, Current opinion in cell biology.

[15]  A. Italiano,et al.  Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  Thomas Kirchner,et al.  Migrating cancer stem cells — an integrated concept of malignant tumour progression , 2005, Nature Reviews Cancer.

[17]  H. Ueno,et al.  A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo‐fragments around budding foci , 2005, Histopathology.

[18]  M. Roh,et al.  Intensity of Tumor Budding and Its Prognostic Implications in Invasive Colon Carcinoma , 2005, Diseases of the colon and rectum.

[19]  L. Schwartz,et al.  Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  S. Y. Park,et al.  Tumor Budding as an Indicator of Isolated Tumor Cells in Lymph Nodes From Patients With Node-Negative Colorectal Cancer , 2005, Diseases of the colon and rectum.

[21]  J. Segall,et al.  Molecular mechanisms of invadopodium formation: the role of the N-WASP–Arp2/3 complex pathway and cofilin , 2005 .

[22]  C. Ko,et al.  Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. , 2005, Journal of the National Cancer Institute.

[23]  J. Baselga,et al.  Targeted therapy in advanced colon cancer: the role of new therapies. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Thomas Kirchner,et al.  Down-Regulation of the Homeodomain Factor Cdx2 in Colorectal Cancer by Collagen Type I , 2004, Cancer Research.

[25]  J. Massagué,et al.  Epithelial-Mesenchymal Transitions Twist in Development and Metastasis , 2004, Cell.

[26]  S. Störkel,et al.  Immunohistochemical Detection of EGFR in Paraffin-embedded Tumor Tissues , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[27]  N. Hynes,et al.  The ErbB receptors and their role in cancer progression. , 2003, Experimental cell research.

[28]  B. Leggett,et al.  APC mutation and tumour budding in colorectal cancer , 2003, Journal of clinical pathology.

[29]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[30]  H. Ueno,et al.  Tumour `budding' as an index to estimate the potential of aggressiveness in rectal cancer , 2002, Histopathology.

[31]  N. Goldstein,et al.  Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma , 2001, Cancer.

[32]  R. Nicholson,et al.  EGFR and cancer prognosis. , 2001, European journal of cancer.

[33]  R. Knuechel,et al.  Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[35]  G. Landberg,et al.  Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters. , 2000, The American journal of pathology.