KRAS, BRAF, PIK3CA* Array - Targeted mutation profiling

Colorectal cancer (CRC) is the third most common cancer worldwide and prognosis for patients with metastatic CRC (mCRC) remains poor, with a median overall survival (OS) of 18 to 21 months.₁₋₃ Monoclonal antibodies like cetuximab and panitumumab have proven to be effective in combination with chemotherapy or as single agents for the treatment of mCRC. They block the signal from EGFR inhibiting downstream signalling including KRAS, BRAF and PIK3CA* mediated events.

However, when KRAS, BRAF and PIK3CA* are mutated they are permanently ‘turned on’, permitting downstream signalling, irrespective of anti-EGFR therapy. The Randox KRAS, BRAF, PIK3CA* Array allows the clinician to detect important mutations in these genes, enabling the appropriate selection of patients for therapy.

Studies have shown that patients with mCRC carrying activating KRAS gene mutations do not benefit from anti-EGFR moAb therapy and KRAS mutations have emerged as the major negative predictor of efficacy in patients receiving cetuximab or panitumumab. The occurrence of KRAS mutations however only accounts for 35-45% of nonresponsive patients. Identification of additional genetic determinants of primary resistance to EGFR targeted therapies in CRC is therefore important. Recent studies have shown mutations in BRAF and PIK3CA genes to affect patient response to EGFR-targeted moAbs. ₃₋₆

In addition to colorectal cancer, KRAS, BRAF and PIK3CA* mutations have been implicated in lung cancer, head and neck cancer, malignant melanoma and breast cancer. ₆ ₋ ₈

The KRAS, BRAF, PIK3CA* Array is designed for the rapid qualitative simultaneous detection of point mutations within the KRAS, BRAF and PIK3CA* genes from fresh/frozen and formalin fixed paraffin embedded (FFPE) tissue DNA for predictive and prognostic mutation profiling. *PIK3CA for research use only

Key Benefits

  • Compatible with FFPE tissue and fresh/frozen tissue
  • Detection of 1% mutant in a background of wildtype genomic DNA
  • Only a single DNA sample required
  • Mutations are also implicated in other cancers such as KRAS in lung cancer, BRAF in malignant melanoma and PIK3CA in breast cancer

References

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  • Centers for Disease Control and Prevention: United States Cancer Statistics: US Cancer Statistics Working Group. http://www.cdc.gov/uscs.
  • Bardeli, A. Siena, S. (2010) Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal Cancer. Journal of Clinical Oncology 28, 1254-1261.
  • Saltz, L.B., Meropol, N.J., Loehrer, P.J. Sr, et al. (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expressed the epidermal growth factor receptor. Journal of Clinical Oncology 22, 1201-1208.
  • Cunningham, D., Humblet, Y., Siena, S., et al. (2008) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine 358, 1160-1174.
  • Shi, C. Washington, K. (2012). Molecular Testing in Colorectal Cancer. Am J Clin Pathol 2012; 137: 847-859.
  • Riley, G.J., Marks, J., Pao, W. (2009). KRAS Mutations in Non-Small Cell Lung Cancer. Proc Am Thorac Soc. Vol 6. Pp 201-205
  • Gonzalez de Castro, G. Clarke, PA., Al-Lazikani, B., Workman, P. (2013). Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance. Nature Vol 93 No 3 pp.252-259.
  • Board, R.E., Wardley, A.M., Dixon, M. et al. (2010). Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Research and Treatment. Vol 120, Issue 2, pp 461-467.