KRAS

The KRAS gene is a proto-oncogene responsible for the production of the KRAS protein. Proto-oncogenes typically play a role in regulating normal cellular processes and when mutated (now called an oncogene), have the potential to cause cancer.

A wild-type KRAS (or normal) protein acts as an “on-and-off switch” involved in controlling cell growth, proliferation (division), and survival. Mutated KRAS protein acts as an “on switch” resulting in uncontrollable cell growth and proliferation, which can lead to cancer.

The most common mutations in KRAS are G12C, G12D, and G12R. Other common mutations include G12A, G12S, G12V, G13C, and G13D.

These mutations are written to represent the location and types of amino acid being mutated within the protein. The letters represent the amino acids, building blocks of protein, that are made when a gene is mutated. The number refers to the location of the mutation. The location can be thought of as the codon or the amino acid location – as codons are three nucleotide sequences in messenger RNA (mRNA) transcripts that “call” for a specific amino acid.

Using G12C as an example, G and C represent the amino acids. In this case, glycine (G) got replaced by cysteine (C), while 12 refers to the 12th codon in a mRNA transcript or amino acid in the protein sequence.

All patients with stage IV metastatic colorectal cancer should have their tumors tested for KRAS mutations. Patients with recurrent colorectal cancer should also have their tumors be tested for KRAS mutations. Tumor KRAS mutation testing is also useful in patients being considered for EGFR inhibitor treatment.

The most common method for testing KRAS is using a tumor biopsy sample from the primary or metastatic tumor. Alternatively, a blood sample using circulating tumor DNA (ctDNA), also called a liquid biopsy may be used. KRAS may be tested individually or as part of a multi-gene panel.

The best way to ensure your tumor has have been tested for KRAS mutations is to ask your medical care provider.

A report for your tumor’s KRAS biomarker may be reported as “KRAS wild-type” or “KRAS WT” if there is no KRAS mutation present. If there is a KRAS mutation present, it may be listed as “KRAS mutant” or with the specific mutation, such as “KRAS G12C mutation” or “KRAS codon 12 mutation.”

KRAS mutations are found in about 40% of colorectal cancers. This means approximately 60% of colorectal cancers have wild-type (WT) KRAS. KRAS mutations involved in colorectal cancer are not hereditary.

If your tumor has have wild-type KRAS, it you does not have a mutation within your KRAS gene.

• Patients with wild-type KRAS tumors often benefit from targeted treatment with EGFR inhibitors (or anti-EGFR therapies).
• Patients with wild-type KRAS tumors typically have a more favorable prognosis than those with KRAS mutations.

If you have a tumor with mutant KRAS, you have a mutation within your KRAS gene.

• Patients with mutant KRAS tumors often do NOT respond to targeted EGFR inhibitors and they are not recommended. Why not? EGFR inhibitors block the epidermal growth factor receptor (EGFR). Typically, wild-type RAS proteins are turned “on” or activated by EGFR. However, mutant RAS proteins are often always turned “on” or constitutively active. So, even if EGFR is inhibited by targeted therapies, mutant RAS proteins will still be “on” or active.
• Treatment options for patients with mutant KRAS tumors often include traditional chemotherapy combinations. If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with KRAS mutant colorectal cancer.
• Colorectal cancers with KRAS mutations are often more aggressive with a higher risk of occurrence. You should talk to your medical team about how you will be checked for recurrence during your follow-up care.

The FDA has approved adagrasib (KRAZATI^®) in combination with cetuximab as a targeted treatment option for stage IV patients with the KRAS G12C mutation. These patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

A KRAS-mutant colorectal cancer is often treated with traditional chemotherapy (FOLFOX, FOLFIRI, CAPOX) with or without bevacizumab.

If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with KRAS mutant colorectal cancer.

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you.

FDA Approved Treatments to consider if I am KRAS wild-type

EGFR inhibitors, such as cetuximab or panitumumab, may be used as a stand-alone treatment or in combination with other traditional therapies (FOLFOX or FOLFIRI).

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you.

Drugs targeting KRAS mutations are being tested in clinical trials. Talk to your medical team to determine if you may benefit from a clinical trial.

Check out Fight CRC’s Clinical Trial Finder to search for KRAS-positive trials, and read our Clinical Trials Conversations for important updates.