Colorectal cancer is a leading cause of cancer death for both men and women in the United States. Usually, colorectal cancers develop slowly over a period of years, beginning as precancerous polyps. More than 95% of colorectal cancers are adenocarcinomas, which begin in mucosal cells of the intestinal lining. Gastrointestinal stromal tumors (GIST) may also arise in the colon. There are an estimated 150,000 patients in the US diagnosed with colon cancer each year of and 50,000 reported deaths.*
Treatment options for metastatic colorectal cancer have expanded beyond chemotherapy with the development of targeted therapies aimed at faulty genes or proteins involved in the growth and progression of tumors. For colorectal cancer, targeted therapies fall into the anti-angiogenesis (VEGF) class or anti-growth (EGFR) class. These therapies may be used as mono-therapy or in combination with existing chemotherapy regimes.
The drug target Epidermal Growth Factor Receptor (EGFR) protein activates the RAS/RAF/MAPK, STAT, and PI3K/AKT signaling pathways, which together control cellular proliferation, adhesion, angiogenesis, migration and survival. Current approved EGFR inhibitor therapies for colorectal cancer include cetuximab and panitumumab. Both therapies are monoclonal antibodies which bind and block the EGFR malignant signaling activity.
Several clinical studies have demonstrated that colorectal tumors which harbor constitutively active oncogenic KRAS mutations show resistance to anti-EGFR targeted therapy.1 KRAS is a small downstream GTP-binding protein. Resistant KRAS mutations that lead to lack of response to anti-EGFR therapy are located in codons 12 and 13.
Clinical trials related to anti-EGFR drug development will benefit from classifying tumors from colorectal patients as either wild type or mutated form by identifying those patients that are most likely to respond.
As a leader in developing complex molecular diagnostic tests, MolecularMD has developed a menu of KRAS mutational detection testing (including exon 1 mutations listed above and, more recently, mutations for exon 2, codons 58, 59, 60, 61) for colorectal and other solid tumor samples.
*US-based statistics
1Chang DD, et al. J Clin Oncol, Vol 2008;26(10):1626-1634