What is the NRAS biomarker?

NRAS is a member of the RAS family of genes, along with KRAS and HRAS. These genes, which encode (give the instructions for cells to make) the Ras proteins, play an important role in the way that cell growth, cell proliferation, and cell differentiation are controlled. Cell growth is an increase in cell size, cell proliferation is an increase in the number of cells, and cell differentiation is the process in which immature (unspecialized) cells become mature (specialized) cells. Genetic alterations (mutations) in RAS genes can cause cells to grow abnormally and become cancer by disrupting the cell’s normal control pathways (signal pathways). Genes, like NRAS, that can cause normal cells to become tumor (tumour) cells are called oncogenes. The NRAS gene mutations found in colorectal (bowel) cancer are somatic, which means they occur in non-reproductive cells and are not hereditary.  

NRAS is both a prognostic and predictive biomarker. It gives information about the usual course of disease (prognosis) and it is a predictor of which treatments may be more or less effective against a particular colorectal cancer, such as conventional chemotherapy drugs or targeted therapy with EGFR inhibitors.  

Similar to KRAS mutations, NRAS mutations play a role in several human cancers. The incidence of NRAS mutation in all solid tumors is 3%, while NRAS mutations are found in 5% of colorectal cancers and 20% of melanomas.  

How is the NRAS biomarker tested?

The recommended method of testing for NRAS mutation status is with a biopsy sample of tumor cells, either from the primary colorectal carcinoma tumor or from tumor metastases. The cancer cells are treated in a laboratory to isolate the tumor DNA to be studied.  

NRAS may also be tested in a blood sample by examining circulating tumor DNA (ctDNA). This is called a liquid biopsy. NRAS mutations may be tested individually, or as part of a multi-gene panel using next-generation sequencing (NGS). NRAS biomarker testing is sometimes referred to as NRAS mutation analysis or NRAS gene sequencing.

What do my NRAS biomarker test results mean?

If your NRAS biomarker result is reported as “NRAS wild-type” or “NRAS WT” this means there is no NRAS mutation in your cancer. Wild-type is the normal state of the gene.

If there is an NRAS mutation in your cancer, it will be reported as “NRAS mutant” or its specific mutation will be listed, for example “NRAS Q61K mutation”, “NRAS codon 12 mutation” or “NRAS exon 3 mutation”.

What is the impact of NRAS mutation testing on my treatment?

If your tumor has NRAS wild-type (no mutation)

• Patients whose colorectal cancer has NRAS wild-type benefit from targeted treatment with EGFR (epidermal growth factor receptor) inhibitors.  
• Cetuximab (Erbitux) and panitimumab (Vectibix) are EGFR inhibitors used in treating NRAS wild-type colorectal cancers. They are sometimes called anti-EGFR drugs or anti-EGFR monoclonal antibodies.  

If your colorectal cancer has an NRAS mutation

• Colorectal cancers with NRAS mutations may be aggressive and have a higher risk of recurrence. Talk to your oncology team about how you will be checked for recurrence during follow-up care.
• When NRAS mutations are present, treatment options include traditional chemotherapy combinations (for example FOLFOX, FOLFIRI, CAPOX).
• Conventional chemotherapy drugs are sometimes combined with bevacizumab (Avastin), which is a targeted therapy that prevents the formation of new blood vessels to supply the tumor with nutrients.  
• If indicated by other biomarker testing results, such as microsatellite instability (MSI), immunotherapy drugs, like nivolumab (Opdivo), pembrolizumab (Keytruda), and ipilimumab (Yervoy), may be used in patients with NRAS mutant cancer.
• Other targeted treatments for NRAS mutant colorectal cancer may be recommended based on the results of other biomarker testing (such as BRAF inhibitors and MEK inhibitors in colorectal cancer subtypes with BRAF mutation).
• NRAS mutant colorectal cancer is resistant to EGFR inhibitors, and they are not recommended unless in combination with other targeted therapies.

There are currently no approved therapies directly targeting NRAS mutations in colorectal cancer. However, there are ongoing clinical trials for targeted treatments for NRAS wild-type and NRAS mutant cancers. Talk to your healthcare team about whether you could benefit from participation in a clinical trial.

Who should have biomarker testing for NRAS?

If you have stage IV / metastatic colorectal cancer, you should have testing for NRAS mutation status.

If your healthcare team is considering EGFR inhibitor treatment, you should be tested for NRAS mutations.