What is a biomarker | Know Your Biomarker

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A biomarker (also called a biological marker) 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. Biomarkers can tell your medical team important information about you and your cancer.

What is a colorectal cancer biomarker?

For colorectal cancer (which refers to colon cancer, rectal cancer, and bowel cancer), relevant biomarkers include:

Substances released by your cancer into your blood. This includes tumor enzymes and other tumor proteins, as well as circulating tumor DNA (ctDNA).
Location of your tumor. Colorectal cancer (CRC) can be located in the right side of the colon, or in the left side of the colon and the rectum.
Changes (mutations) in the genes of your tumor (tumour) cells and mutations in the genes of some or all of your other cells. Mutations in your tumor genes and in your non-cancer cells can be involved in causing cancer. Other mutations may affect your cancer’s invasiveness or tendency to spread, changing your prognosis. Some tumor mutations influence how your cancer responds to different treatments.
Mutations that occur in your tumor cells or in your non-reproductive body cells are called somatic mutations. Somatic mutations are not inherited.
Mutations that occur in reproductive cells (sperm and egg). These are called germline mutations and they are passed on to children. 5% of colorectal cancers are caused by germline mutations, which means they are hereditary.

Why are biomarkers important?

Colorectal cancer biomarkers can provide your medical team vital information about you and your cancer that is used to determine prognosis, guide treatment decisions, monitor treatment response, and look for recurrence after treatment. Biomarkers are also used in drug development to create and test targeted therapies for colorectal cancer.

How are biomarkers and biomarker
testing used?

Prognosis

Prognosis is the expected course of a disease. Biomarkers can indicate the overall prognosis of your cancer and your risk of cancer recurrence after treatment.

Treatment Decisions

Some predictive biomarkers can indicate which treatments will be effective or ineffective against your cancer. Other biomarkers can predict which treatments will cause you severe toxic side effects. Biomarkers that predict recurrence after treatment may guide decisions about adjuvant therapy after surgery.

Treatment Response Evaluation

Some biomarkers can be used as surrogate endpoints, which are indicators of how well a treatment is working. Surrogate endpoints are often examined in the short-term setting of clinical practice or clinical trials to predict long-term outcomes like survival or disease progression. In clinical care, measuring a biomarker surrogate endpoint may lead to earlier changes in a treatment that is not working. In clinical trials, surrogate endpoint measurement may allow faster drug approval by regulatory bodies like the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA).

Screening and Recurrence Monitoring

Biomarkers can be used to screen for cancer in people who are at high risk for cancer and can be used in follow-up care to look for recurrence after treatment. New biomarkers are under investigation for the screening of patients with average colorectal cancer risk.

Treatment Development

Biomarkers are used to identify potential targets of colorectal cancer treatments. These targets are often mutations in the genes that encode (provide the instructions for making) enzymes and other proteins involved in abnormal growth and tumor spread. New targeted therapies that disrupt the processes (molecular pathways) of abnormal growth are studied through clinical trials. Clinical trials of cancer treatment always compare new treatments to the standard clinical practice, never a non-treatment placebo.

What is a biomarker test?

A biomarker test is a laboratory test for a genetic mutation in your tumor cells or in your other cells, a measurement of the presence or amount of a substance (DNA or protein) in your tumor tissue or blood, or an imaging test (like a CT scan) of your tumor.

How are biomarkers tested?

Biomarker testing is done by analyzing tumor biopsy tissue, blood samples, or other body fluids. When biomarkers are tested in circulating tumor DNA (ctDNA) from a blood sample, it is called liquid biopsy. Biomarker information can also come from radiologic imaging (CT scans, X-rays, MRI scans), or surgical reports.

What types of biomarkers can be tested in colorectal cancer patients?

Colorectal cancer biomarkers that give prognostic information, help guide treatment decisions, and allow monitoring for treatment response or recurrence after treatment

Microsatellite stability (MSS) describes your tumor cells’ ability to do DNA mismatch repair. DNA mismatch repair is the correction of mistakes that occur in DNA when cells grow and divide.
Microsatellite instability (MSI-High) describes your tumor cells’ deficiency in DNA mismatch repair (also called dMMR). Your tumor cells are unable to correct some mistakes that occur in DNA when cells grow and divide.
KRAS, a member of the RAS family of genes, is involved with control of cell growth and cell survival. Wild-type (normal, non-mutant) KRAS tumors may be treated with EGFR inhibitors. There are ongoing clinical trials testing KRAS-specific therapeutic intervention for colorectal cancer with KRAS mutation, and KRAS mutant tumors may be treated with traditional chemotherapy and targeted therapies.
NRAS, a member of the RAS family of genes, is involved in control of cell growth and cell survival. Tumors with no NRAS mutation (normal, wild-type) may be treated with EGFR inhibitors. NRAS mutant colorectal cancer may be treated with traditional chemotherapy and targeted therapies. Ongoing clinical trials are studying NRAS-specific targeted therapy.
BRAF is a gene involved in control of cell growth. Tumors with BRAF mutations may be treated with BRAF inhibitors, a targeted therapy.
Carcinoembryonic antigen (CEA) is a protein made by most but not all colorectal cancers. Measuring CEA before, during, and after cancer treatment can provide information about how well a treatment is working, whether your cancer is progressing, and whether you may have a cancer recurrence.
HER2 is a gene that encodes (gives instructions for making) a protein involved in cell growth and cell survival. HER2 gene amplification or protein overexpression can lead to uncontrolled cell growth and survival of abnormal cells that should die. Colorectal cancer that has HER2 amplification or overexpression can be treated with targeted therapy using HER2 inhibitor drugs.
Tumor mutational burden (TMB) is a measurement of how many mutations there are in your tumor’s genes (tumor DNA), rather than a test of a specific mutation. Patients with TMB-High may be candidates for immunotherapy, even patients who have the MSS biomarker which is not typically treated with immunotherapy.
NTRK fusion is a mutation in which one of the three NTRK genes is fused with a partner gene on another chromosome, creating TRK fusion proteins. It is rare in colorectal cancer, but patients with MSI-High, TMB-High, and wild-type KRAS, NRAS, and BRAF have higher rates of NTRK fusion. NTRK fusion positive patients may be treated with targeted therapy with TRK inhibitors.
PIK3CA is a gene involved in the control of cell growth, cell survival, and cell migration. PIK3CA inhibitors, which are treatments that target PIK3CA mutations, are already in use in breast cancer, and are being tested for colorectal cancer in ongoing clinical trials.
Tumor location / tumor sidedness. Colorectal tumors can be right-sided (also known as proximal), located in the cecum through the transverse colon, or left-sided (also known as distal) located in the splenic flexure through the rectum. Tumor location is associated with different biomarker mutations, different patient sex, different age groups, different hereditary colorectal cancer syndromes, and different patterns of metastasis.

Biomarkers of hereditary colorectal cancer

The biomarkers that can confirm hereditary colorectal cancer are the DNA mismatch repair genes causing Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer), and the genes causing Familial Adenomatous Polyposis (FAP) and associated syndromes. Lynch Syndrome is caused by mutations in MLH1, MSH2, MSH3, MSH6, EPCAM, or PMS2 genes, while FAP and other polyposis syndromes are caused by mutations in APC, MYH, BMPR1A, and SMAD4.

Lynch Syndrome

Learn about Lynch Syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), a cancer syndrome caused by deficient DNA mismatch repair (dMMR).

+ Read more

Familial Adenomatous Polyposis (FAP)

Learn about familial adenomatous polyposis (FAP), an inherited genetic colorectal cancer syndrome, and how it affects you and your family.

+ Read more

Treatment toxicity biomarkers

Treatment toxicity biomarkers that can be tested to give you and your healthcare team information about the risk of severe or life-threatening side effects from cancer drugs. These are UGT1A1, an enzyme needed for metabolism of fluorouracil (5-FU) based chemotherapy drugs and DPYD, an enzyme required for metabolism of irinotecan and irinotecan-related chemotherapy drugs.

Who should have biomarker testing?

Everyone with colorectal cancer should have biomarker testing.

The exact biomarker tests needed can vary by:

What cancer stage you have. Some tests are recommended at all stages of colorectal cancer, while others are recommended only in advanced or Stage IV / metastatic cancer.
Whether you’ve been treated for CRC before, what kind of cancer treatment you had, and what your treatment outcome was. For example, patients who have progressed on EGFR inhibitors but then have a break from these drugs may have KRAS and NRAS tests in the form of liquid biopsy to guide the decision to try EGFR inhibitors again.
Your personal and family cancer history, including non-colorectal types of cancer, which may suggest you have a hereditary cancer syndrome like Lynch Syndrome or Familial Adenomatous Polyposis.
The results of any previous biomarker testing you have had. For example, patients with the biomarker result MSI-High need to be tested for Lynch Syndrome.

All CRC patients, no matter the stage at diagnosis, should be tested for microsatellite stability / instability (MSS / MSI) biomarker testing. [Recommended by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO).]

If you have stage IV / metastatic colorectal cancer, you should have testing for RAS (both KRAS and NRAS), and BRAF. [Recommended by NCCN and ESMO.]

If you have stage IV / metastatic colorectal cancer you should have HER2 testing. [Recommended by NCCN.]

There are several biomarkers that don’t currently have standardized recommendations for testing, including PIK3CA, tumor mutational burden (TMB), and NTRK gene fusion. Talk to your healthcare team about whether testing these or other specific biomarkers could help you.

What is a Biomarker?

What is a colorectal cancer biomarker?

Why are biomarkers important?