KRAS mutational analysis for identification of patients unlikely to respond to
EGFR targeted antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®)
Colorectal carcinogenesis is a multi-step process involving the accumulation of molecular alterations in a number of genes and pathways of proliferative cells of the colon. These alterations lead to a loss of coordination between the processes of cellular proliferation and differentiation. The epidermal growth factor receptor (EGFR) plays a significant role in cellular pathways that govern differentiation, proliferation, and survival. Aberrations in the EGFR signaling pathway have been observed in a number of cancers including colorectal.1 Cetuximab and panitumumab are monoclonal antibodies that target and can inhibit EGFR activity. However, not all colorectal tumors respond and benefit from these therapies. Recent
discoveries have identified a gene (KRAS), that when mutated, confers resistance to cetuximab and panitumumab by circumventing EGFR’s role in the signaling pathway.
Somatic activating mutations in the KRAS gene of colorectal tumors have been shown to lead to dysregulation of numerous down stream signaling pathways and result in resistance to cetuximab or panitumumab (EGFR-targeted inactivation 2-5).
- KRAS is a proto-oncogene that when mutated leads to a dysfunction of the regulation of cellular control pathways leading to increased proliferation, interference with normal apoptosis, and other processes.6 Oncogenic forms of KRAS cause the protein to be resistant to inactivation, resulting in increased cellular proliferation and resistance to inactivation by EGFR inhibitors.
- Mutated KRAS – a tumor genotype that is resistant to cetuximab and panitumumab.
- Wild type KRAS –a tumor genotype in which KRAS has not been genetically altered. A percentage of patients with this genotype respond to cetuximab or panitumumab.
- KRAS is mutated in 20 to 50% of colon tumors.2-5
- The incidence of mutations in KRAS generally increases with the increasing Dukes’stage or the presence of metastasis.7-8
Caris Dx KRAS Mutational Analysis:
- Provides vital prognostic information identifying those patients whose tumors are resistant to Erbitux and Vectibix
- Detects the 14 most frequent KRAS mutations covering over 99% of known KRAS mutations
- Detects codons 12, 13 and 61
- Testing can be performed on archived specimens (paraffin blocks of tumor)
- Tumor specimens submitted for analysis must contain a minimum of 2 mm of 100% tumor or 4 mm of 50% tumor or an equivalent combination
- A minimum of five (5) micron tissue sections from the specimen should be submitted on uncharged unbaked slides. An unstained slide for H&E analysis must also be included.
- 8 - 10 day turn around
1. Galizia, G., et al., Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol, 2006. 13(6): p. 823-35.
2. De Roock,W., 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(3): p. 508-15.
3. Lievre, A., et al., KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol, 2008. 26(3): p. 374-9.
4. Amado, R.G., et al.,Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol, 2008. 26(10): p. 1626-34.
5. Khambata-Ford, S., et al., Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol, 2007. 25(22): p. 3230-7.
6. Arteaga, C.L., Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol, 2002. 29(5 Suppl 14): p. 3-9.
7. Hsieh, J.S., et al., APC, KRAS, and p53 gene mutations in colorectal cancer patients: correlation to clinicopathologic features and postoperative surveillance. Am Surg, 2005. 71(4): p. 336-43.
8. Andreyev, H.J., et al., Kirsten ras mutations in patients with colorectal cancer: the multicenter ‘RASCAL" study. J Natl Cancer Inst, 1998. 90(9): p. 675-84.