K-ras Mutation Detection in Treatment of Colorectal Cancer
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Colon cancer is the third most frequently detected cancer worldwide, accounting for close to 1 million new patients every year. Colon cancer has the third highest mortality rate, following lung and breast cancer. Seventy to eighty percent of patients have a potentially curative disease; however close to 50% of patients will develop metastases (liver being the most common site).
Resistance to conventional chemotherapy is likely the main reason for disease progression. Less than 10% of patients with disseminated disease will survive for five or more years (1).
Recent publications on colorectal cancer have shown the benefit of using the epidermal growth factor receptor (EGFR) in treatment strategy. EGFR is a trans-membrane glycoprotein and one of the four HER-family tyrosine kinases (EGFR, erbB2, erbB3, erbB4) which initiate intracellular proliferation signaling (2). Epidermal growth factor (EGF), transforming growth factor alpha (TGF-), amphiregulin and betacellulin are the main ligands for EGFR (3).
The activation of EGFR results in cell proliferation and survival through the Ras/Raf/MEK/ERK or PI3K/PTEN/AKT pathways, respectively (1). Activated EGFR also regulates the production of angiogenic factors and permits tumor invasion through extra-cellular matrix components. About 70% of cases with metastatic colorectal cancer have EGFR expression. This correlates with poor prognosis (4). Therefore, these studies open the new approaches to inhibit EGFR through monoclonal antibodies and small molecular inhibitors.
Anti-EGFR targeted antibodies such as cetuximab and panitumumab, administered as monotherapy in colorectal cancer, show response and disease stabilization rates of approximately 10% and 30%, respectively (5;6). However, clinical experience shows that level of EGFR expression as measured by immunohistochemistry does not predict clinical benefits (2;5;7)
K-ras, the human homolog of the Kirsten rat sarcoma-2 virus oncogene, encodes a small GTP-binding protein that acts as a self-inactivating signal transducer by cycling from GDP- to GTP-bound states in response to stimulation of a cell surface receptor, including EGFR (8;9)
The incidence of K-ras mutations is about 30 to 35 % in colon cancer patients. Recent studies showed an inverse correlation between K-ras mutations and response to anti-EGFR therapy (3). Amado RG (10)presented the higher sample-size data which showed that patients with K-ras mutations had 70% progressive disease where wild-type K-ras patients showed 36% progressive disease. For K-ras mutated patients in this study, panitumumab offered no benefit. In a similar smaller-sized study on Cetuximab (11) none of 42 K-ras mutated patients obtained treatment benefit, where as 27 out of 66 wild-type K-ras patients responded to therapy.
Overall, current studies for the first time provided evidence on the critical role of K-ras Mutation Detection in advanced colon cancer as a predictor of evaluation and response to EGFR agents.
Reference List
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Adams R, Maughan T. Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer. Expert Rev Anticancer Ther 2007;7:503-18.
Lievre A, Bachet JB, Le CD, Boige V, Landi B, Emile JF et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-5.
Mayer A, Takimoto M, Fritz E, Schellander G, Kofler K, Ludwig H. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993;71:2454-60.
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45.
Van CE, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-64.
Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803-10.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11-22.
Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308.
Amado RG, Wolf M, Peeters M, Van CE, Siena S, Freeman DJ et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626-34.
De RW, Piessevaux H, De SJ, Janssens M, De HG, Personeni N et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508-15.
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