Colorectal Cancer Biomarkers

Biomarkers (short for biological markers) are molecules found in body tissues and fluid, including tumour tissue and blood. They are sometimes referred to as tumour markers or molecular markers. When certain biomarkers are present, it tells your doctors valuable information about your cancer.

Treating colorectal cancer today is different than it was a few decades ago. In the past if you had colorectal cancer, you might have received the standard therapy used for all people with colorectal cancer. We now understand that two people with colorectal cancer may have very different kinds of tumours at the molecular level that will respond differently to therapies.

Biomarkers for Personalized Cancer Care

The use of biomarkers has helped to create a more personalized approach to cancer care that will be the most beneficial to you with the least amount of side effects.

There are different categories of biomarkers that give different information about cancer. Some can tell your doctors about how a tumour might behave in the future in response to treatment, while others can indicate whether cancer cells are still present in a patient after treatment.

Biomarkers For Personalized Cancer Care

Biomarkers

The use of biomarkers has helped to create a more personalized approach to cancer care that will be the most beneficial to you with the least amount of side effects.

There are different categories of biomarkers that give different information about cancer. Some can tell your doctors about how a tumour might behave in the future in response to treatment, while others can indicate whether cancer cells are still present in a patient after treatment.

What is biomarker testing and when is it done?

Biomarker testing looks for genes, proteins, and other substances (called biomarkers or tumour markers) that can provide information about cancer. It is sometimes called molecular testing, tumour testing, or genomic testing. The best time to do testing is soon after a colorectal cancer diagnosis and before a treatment plan is chosen. Even if you were not able to do biomarker testing before you started treatment, it may still be worthwhile to do since it could affect how your current treatment plan progresses.

After a colorectal cancer diagnosis, surgery may be performed to do a biopsy of the tumour. A biopsy removes a small piece of the tumour to examine its characteristics. Then, the tumour is tested in a laboratory for the known biomarkers that impact colorectal cancer patients.

Learn more about specific resources related to biomarker testing through our Get Personal Program.

Colorectal Cancer Biomarkers

BRAF V600E refers to a specific mutation in the BRAF gene, which is involved in cell division. With the V600E mutation, the BRAF gene drives the proliferation of cancer cells, and has been linked to poor disease outcomes in patients. Patients with BRAF V600E mutations do not respond well to EGFR inhibitors.

The BRAF-inhibitor Encorafenib (Braftovi®) in combination with the EGFR-inhibitor cetuximab (Erbitux®) has show positive results in the treatment of BRAF V600E metastatic colorectal cancer. The combination therapy has recently been approved in the United States for this subset of colorectal cancer patients.

Some patients with BRAF V600E-mutated colorectal cancer also have microsatellite instability, which means that this subset of patients may be responsive to immunotherapy drugs such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®).

In metastatic colorectal cancer, mutations of the BRAF gene most commonly are V600E. Non-V600E BRAF mutations occur in about 1% of metastatic colorectal cancer patients. Similar to patients with mutated KRAS or NRAS genes, patients with a BRAF mutation may not respond well to EGFR inhibitors, nor to standard chemotherapy.

KRAS (Kirsten rat sarcoma) is a gene that is involved in promoting the growth and division of colorectal cancer cells. It is part of a pathway in the cell that relies on a specific receptor found on the surface of cells called the epidermal growth factor receptor (EGFR). When KRAS is abnormal or mutated as in 35-45% of colorectal cancer patients, the class of targeted therapy drugs known as EGFR inhibitors may not be a useful treatment.

The natural, unchanged form of the KRAS gene is referred to as KRAS wild-type. Patients whose biomarker test shows that the tumour is KRAS wild-type may respond well to treatment plans that include EGFR inhibitors.

NRAS is a gene that is involved primarily in regulating cell division and like KRAS, is also involved in the EGFR-mediated pathway in the cell. NRAS mutations occur in less than 5% of colorectal cancer tumours. Similar to KRAS, if a patient’s biomarker test shows an NRAS mutation, EGFR inhibitors may not be a useful treatment.

The natural, unchanged form of the NRAS gene is referred to as NRAS wild-type. Patients whose biomarker test shows that the tumour is NRAS wild-type may respond well to treatment plans that include EGFR inhibitors.

The PIK3CA gene is involved in cell growth and division. Mutations in this gene have been associated with minimal benefits from EGFR inhibitors.

Carcinoembryonic antigen (CEA) is one of the most widely used biomarkers in the world. It is a protein that is found on the surface of colorectal cancer cells. CEA tests may be used to find out if cancer treatment is working, or to find out if cancer has come back after treatment.

After treatment, a return to a normal CEA level that was previously high usually means that the cancer has responded to treatment. A CEA level that rises after treatment has ended usually means that the cancer has come back.

CEA blood level may also increase in non-cancerous conditions such as inflammatory conditions of the colon or rectum, such as ulcerative colitis.

Circulating tumour DNA (ctDNA) are small pieces of DNA present in the bloodstream which originate from tumour cells. Most DNA is contained within the cell’s nucleus. As a tumour grows, however, cells will die and get broken down. Their contents, including DNA, are then released into the bloodstream. The quantity of ctDNA can vary among individuals and will depend on the tumour type, its location, and the cancer stage. Testing for ctDNA is sometimes referred to as liquid biopsy.

Detection of ctDNA can be helpful in the following ways:

  • Detecting and diagnosing a tumour
  • Guiding a more personalized approach to cancer treatment
  • Monitoring treatment, where a decrease in the quantity of ctDNA suggests that the tumour is shrinking and treatment is working
  • Monitoring cancer recurrence, where a lack of ctDNA in the blood suggests that the cancer has not returned.

In Canada, some tests detecting ctDNA are already being used but they remain reserved for people with a known cancer diagnosis. For example, one test screens for ctDNA from people with advanced cancer to look for for specific mutations that could be selectively targeted by available drugs. Liquid biopsy is especially useful when a tissue biopsy is not possible. Current research aims to refine ctDNA screening tests to expand their use to early cancer detection.

HER2 is a gene that is involved in cell division. Increased levels of HER2 expression is found in about 2-6% of patients with stage 3 or 4 colorectal cancer. The presence of a HER2 mutation has been associated with poor response rates to EGFR inhibitors.

Trastuzumab Detuxtecan (T-Dxd) is a targeted therapy drug approved for the treatment of HER2-positive metastatic breast cancer. It has been shown to also be effective in HER2-positive metastatic colorectal cancer. The phase II DESTINY-CRC01 study found that the treatment provided an overall survival benefit for this subset of colorectal cancer patients compared to the standard of care.

Microsatellite Instability – high (MSI-H)/mismatch repair deficient (dMMR) is a status that is given to patients when the genes that fix DNA errors as it is dividing, the mismatch repair genes, are unable to do their job. When these genes are not functioning properly, the DNA can become unstable because of the errors and can lead to various kinds of cancer including colorectal. If this instability is present in a tumour, it is classified as MSI-H.

About 25% of MSI-H or dMMR tumours are associated with the hereditary syndrome, Lynch syndrome. About 5% of patients with metastatic colorectal cancer will have MSI/dMMR tumours. This subset of patients is more likely to benefit from immunotherapy treatment, such as nivolumab (Opdivo®) or pembrolizumab (Keytruda®).

Where colorectal cancer is located in the colon can impact a patient’s disease outcomes. Tumours that are found in the right side of the colon compared to the left side of the colon show different characteristics at the molecular level. As a result, left-sided and right-sided tumours tend to respond differently to treatment.

When the NTRK gene joins or “fuses” with an unrelated gene, it produces signaling in the cell that can cause cancerous tumours to grow. While TRK fusions are very rare, if they are detected they present a possible treatment option with drugs that specifically target NTRK-fusion positive metastatic colorectal cancer, such as entrectinib (Rozlytrek®) and larotrectinib (Vitrakvi®) .