KRAS biomarker and colorectal cancer

KRAS is a gene that helps control how cells grow and divide. It is part of a group of genes called the RAS family, which also includes NRAS and HRAS.

Normally, the KRAS protein acts like an “on-and-off switch” for cell growth. A mutation can cause the switch to remain turned on, sending continuous signals that encourage cancer cells to grow.

A KRAS mutation is called a driver mutation because it can help drive the development and growth of a tumor.

KRAS mutations are found in approximately 40% to 45% of colorectal cancers. Common KRAS mutations include G12D, G12V, G13D, G12C and G12A. The letters and numbers identify the exact location and type of change in the KRAS protein.

The KRAS mutation identified through colorectal cancer biomarker testing is usually a somatic mutation. This means it developed in the tumor and is not generally something a person was born with or can pass to their children.

Tumor biomarker testing is different from testing for inherited cancer risk. Your care team may recommend genetic counseling or separate germline testing based on your age at diagnosis, family history, or other findings.

A  KRAS wild-type result means the laboratory did not find a tested mutation in the KRAS gene.

However, KRAS is only one part of RAS testing. A tumor may be considered RAS wild-type only when no relevant mutation is found in either KRAS or NRAS.

Knowing whether a tumor is RAS-mutated or RAS wild-type helps your care team determine whether certain targeted treatments may be effective.

People with metastatic colorectal cancer (stage IV) should have their tumors tested for KRAS and NRAS mutations. Ideally, testing should be completed before treatment decisions are made, especially before considering medicines that target EGFR.

Comprehensive, or extended, RAS testing generally examines important areas of KRAS and NRAS known as exons 2, 3, and 4. These include several different mutation locations, not only KRAS codons 12 and 13.

Testing may use:

• Tissue collected during a biopsy or surgery
• A blood-based test, sometimes called a liquid biopsy
• A broad biomarker panel that looks at many cancer-related genes at once

A blood test can sometimes miss a mutation when there is not enough tumor DNA in the bloodstream. If the blood result does not identify a mutation, your doctor may recommend testing tumor tissue when available.

Your KRAS and NRAS results help your care team choose treatments that may work best for you.

If the tumor is RAS wild-type, medicines that target EGFR, such as cetuximab or panitumumab, may be an option. These medicines may be given alone in some later treatment settings or with chemotherapy. In first-line treatment, anti-EGFR therapy is most strongly recommended for certain patients with RAS wild-type metastatic colorectal cancer that began on the left side of the colon or in the rectum.

Anti-EGFR medicines generally do not work when a KRAS or NRAS mutation is present.

If a tumor has a KRAS or NRAS mutation, treatment may include chemotherapy, medicines that target tumor blood vessels, surgery or other local treatments when appropriate, and therapies based on additional biomarkers.

For some adults with previously treated advanced or metastatic colorectal cancer and a KRAS G12C mutation, FDA-approved targeted treatment combinations include:

• Adagrasib with cetuximab, after prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy
• Sotorasib with panitumumab, after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy

These treatments block KRAS G12C and EGFR at the same time.

Approved KRAS-targeted treatments in colorectal cancer currently apply to KRAS G12C. Researchers are studying treatments for other KRAS mutations, including G12D and G12V, as well as medicines designed to target several types of KRAS or RAS mutations.

Clinical trials are an important treatment option for people with KRAS-mutated colorectal cancer, including those whose exact mutation does not currently have an approved targeted therapy.

Research approaches include:

• Medicines designed for specific mutations, such as KRAS G12D or G12V
• Treatments that may block several KRAS or RAS mutations
• Combinations that target more than one cancer-growth pathway
• Immune-based treatments designed to help the immune system recognize KRAS-mutated cancer cells
• Vaccines and cell therapies directed at specific KRAS mutations

Ask about clinical trials early and whenever a treatment decision is being made. Trial eligibility may depend on the exact KRAS mutation, other biomarker results, previous treatments, cancer location and overall health.

• What exact KRAS mutation was found?
• Were both KRAS and NRAS fully tested?
• Is my tumor RAS-mutated or RAS wild-type?
• Were MSI/MMR, BRAF, HER2 and other recommended biomarkers tested?
• Does the location of my original tumor affect my treatment options?
• Is there an approved treatment for my exact mutation?
• Are there clinical trials that match my biomarker results?