KRAS is a member of the RAS family of genes, along with NRAS and HRAS. These genes play an important role in the way that cell growth and cell survival are controlled. Mutations in these genes can cause cells to grow abnormally, and become cancer. Genes, like KRAS, that can cause normal cells to become tumor (tumour) cells are called oncogenes. The KRAS gene mutations found in colorectal (bowel) cancer are not hereditary. (The term KRAS is short for Kirsten rat sarcoma virus. The KRAS gene was first discovered in a sarcoma-causing virus in rodents, but the KRAS discussed here is the human version (homolog) of that gene which is not related to rodents or viruses.)
KRAS is both a prognostic and predictive biomarker. It gives information about the usual course of disease (prognosis) and it predicts which treatments may be more or less effective against a particular colorectal cancer, such as conventional chemotherapy drugs or targeted therapy with EGFR inhibitors. The KRAS gene is a factor in many cancers. The prevalence of KRAS mutations is 40% in colorectal cancer, 20-40% in non-small cell lung cancer (NSCLC), and more than 90% in pancreatic ductal cancer.
The recommended method of testing KRAS is with a tumor biopsy sample, either from the primary colorectal adenocarcinoma tumor or from a metastatic tumor. KRAS may also be tested in a blood sample by examining circulating tumor DNA (ctDNA) for KRAS mutations. This is called a liquid biopsy. It may be tested individually, or as part of a multi-gene panel using next-generation sequencing (NGS).
If your KRAS biomarker result is reported as “KRAS wild-type” or “KRAS WT” this means there is no KRAS mutation in your cancer.
If there is a KRAS mutation in your cancer, it will be reported as “KRAS mutant” or its specific mutation will be listed, for example “KRAS G12C” or “KRAS G12V”.
If your KRAS is wild-type (no mutation)
If your KRAS has a mutation
There are currently no approved therapies directly targeting KRAS mutations in colorectal cancer. However, a KRAS inhibitor has been approved to treat KRAS mutant advanced lung cancer. There are ongoing clinical trials for these targeted treatments in colorectal cancers with KRAS mutations. Talk to your healthcare team about whether you could benefit from a clinical trial.
Acquired resistance is when a treatment that once worked against a tumor stops working. This can be due to new resistance mutations in tumor cells, or due to an increase in the subset of cells with an existing resistance mutation.
EGFR inhibitors are a group of targeted therapy drugs that block the epidermal growth factor receptor (EGFR). EGFR is involved in cell growth. Blocking EGFR can reduce the uncontrolled cell growth and cell proliferation of cancer cells. Cetuximab (Erbitux) and panitumumab (Vectibix) are EGFR inhibitors used in colorectal cancer treatment.
Tumor DNA can change over time, and mutations may occur in the KRAS gene that lead to EGFR inhibitor resistance. Similarly, a tumor that has become resistant to EGFR inhibitors may lose that resistance after stopping the drugs for a period of time. The cancer cells that are EGFR inhibitor resistant may become less common in the tumor, and the cells that are sensitive to EGFR inhibitors can become more common. A change in the KRAS status of your tumor may lead to a change in treatment.
If you have stage IV / metastatic colorectal cancer, you should be tested for the KRAS biomarker.
If your healthcare team is considering EGFR inhibitor treatment, you should be tested for KRAS mutations. In addition, if you have developed EGFR inhibitor acquired resistance and take a break from those drugs, your oncologist may order repeat KRAS testing to see if your tumor continues to be resistant.
A biomarker is a piece of information about your health. Biomarkers include your blood pressure, your blood type, and cholesterol or blood sugar levels measured in a blood test. The biomarkers of cancer are also known as tumor markers.