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KRAS

Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer related deaths. Epidermal growth factor receptor (EGFR) has been validated as a therapeutic target in several human tumors, including CRC. The EGFR signaling pathway is overexpressed in more than 85% of tumors from patients with metastatic colorectal cancer (mCRC). Two anti- EGFR targeted antibodies, Cetuximab (Erbitux®, Imclone) and Panitumumab (Vectibix®, Amgen), have shown promising activity as second-line therapy for mCRC and are used as first line therapy in combination with Oxaliplatin and Irinotecan.

KRAS testing refers to the DNA-based assays that are used to detect mutations in codon 12 or 13 of the KRAS gene. KRAS is the human homolog of the Kirsten rat sarcoma-2 virus oncogene and encodes one of the proteins in the EGFR signaling pathway which plays a critical role in the development and progression of cancer.

Approximately 40% of CRC tumors harbor KRAS mutations. Patients whose tumors have a wild-type sequence of the KRAS gene respond favorably to Cetuximab or Panitumimab, while patients with mutant KRAS are not likely to respond. The presence of KRAS mutations in the tumor is generally associated with a worse prognosis. KRAS testing has the potential to significantly reduce overall health care costs since Cetuximab and Panitumimab are very expensive drugs with an estimated annual cost of $100,000 each. Patients who are unlikely to respond should not be unnecessarily exposed to the potential adverse effects of these drugs which include: rash, pruritus, nail changes, headache, diarrhea, infection, severe allergic reaction and heart attack.

A tumor sample can be fresh, frozen or paraffin-embedded tissue depending on the methodology used. A pathologist needs to confirm that the submitted tissue specimen contains cancer cells and estimate the content of tumor cells (percentage tumor nuclei out of all nuclei present) in the specimen. This estimation of tumor content is important since different KRAS assays have different analytical sensitivities and an attempt should be made to enrich to a level that is acceptable for the assay being used. The DNA is then extracted from the tumor tissue. The two commonly used methods to evaluate samples for KRAS mutations are real-time PCR, using fluorescent probes specific for the most common mutations in codons 12 and 13, and direct sequencing analysis of exon 2 in the KRAS gene. This technique identifies all possible mutations in the exon, but has lower analytical sensitivity than some of the real time PCR assays.

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