KRAS and BRAF

In the US alone, there are over 150,000 newly diagnosed cases each year.  Many of these patients are diagnosed with metastatic colorectal cancer (mCRC).  Although the number of patients surviving 5-years with advance stage mCRC remains small, recent advances may be better able to separate out those that respond to novel cytotoxic and biologic agents versus those that don’t respond to these agents.

Currently treatments for patients with colorectal cancer include several targeted monoclonal antibodies as well as conventional chemotherapeutic agents.   Bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix™), along with conventional chemotherapeutic drugs are some of the most commonly used agents to treat patients with mCRC. 

KRAS has been extensively studied in a wide array of human malignancies, including mCRC. Mutant KRAS can be detected in approximately 30% to 50% of colorectal cancers. The majority of mutations occur at codons 12, 13, and 61 of the KRAS gene on chromosome 12. The Ras-Raf-MAPK pathway lies just downstream of EGFR. The hypothesis suggests that a mutation in KRAS could render cells independent of upstream EGFR activation or inhibition of the receptor through anti-EGFR therapies. Several recent studies now show strong correlation of KRAS mutation with response to panitumumab and cetuximab. These studies show compelling evidence that KRAS mutation is a biomarker of non-responsiveness to either of these drugs in mCRC patients.^1,2

BRAF is a downstream molecule from KRAS in a signaling pathway involved in cell cycling. Both KRAS and BRAF are prone to mutations in sporadic colorectal carcinomas (CRC). Several studies have demonstrated that mutations in KRAS lead to constitutive activation of this pathway, which may lead to cancer progression. This activation results in a failure to respond to anti-EGFR therapy.  KRAS mutations are found in 30-40% of patients who fail to respond to Erbitux (cetuximab) and Vectibix (panitumumab). Data presented at this year’s 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapies demonstrate that BRAF mutations are responsible for an additional 12-15% of patients who fail to respond to anti-EGFR treatment. This finding suggests that testing for the BRAF V600E mutation compliments KRAS mutation analysis and may be as important as KRAS testing for treatment decisions.  As brief overview, the Ras-Raf-MAPK pathway lies just downstream of EGFR.  The hypothesis suggests that a mutation in KRAS could render cells independent of upstream EGFR activation or inhibition of the receptor though anti-EGFR therapies. 

Several recent studies now show strong correlation of KRAS and BRAF mutations with response to panitumumab and cetuximab.  These studies show compelling evidence that KRAS and BRAF mutations are a biomarker of non-response to either of these drugs in mCRC patients. 

Clarient now offers testing for both KRAS and BRAF mutations.

References

1. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1-9, 2008.
   

2. E. Van Cutsem, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 2)