Biomarker Testing

Knowledge is a powerful tool in your fight against colorectal cancer. Treatment planning for patients with colorectal cancer has been dramatically changed thanks to a better understanding of biomarkers.

Biomarkers Mini Magazine

Treatment planning for patients with colon and rectal cancer has been dramatically changed thanks to a better understanding of biomarkers. Knowing a colorectal cancer patient's biomarker status has become an indispensable step in treatment planning. The treatment possibilities for patients have been greatly extended due to biomarker testing, especially for metastatic colorectal cancer patients. 

Work needs to be done to get the word out to patients and healthcare teams to get biomarker tests done. Knowledge is a powerful tool in your fight against colorectal cancer.

Biomarkers 101

What is a biomarker?

Biomarker is a broad term used across disease states and medical practices. Biomarkers describe measurable characteristics that let us know how the body is functioning.

Cancer biomarkers are biological, chemical, or biophysical entities that are present in tumor tissues or body fluids, which can give valuable information about the characteristics of a tumor. They can also provide information about the tumor’s future behavior (how it may grow or react to treatment), as well as give an idea as to whether cancer is still present or not after treatment. 

In terms of understanding why biomarkers are so important in cancer care, it might help to think of them as a roadmap. If you're planning a road trip to somewhere you've never been before, you probably wouldn't start your drive without a map to help guide the way. Maybe you know the general direction, but the specifics to guide your trip are all on the map. Biomarkers work like that map. While you know that you’ll receive some type of cancer treatment, the specific “turns” to take with your treatment plan can be guided by your biomarkers.Biomarkers can help you and your doctor get to a treatment plan more efficiently, just as a map can help you get to your destination more expeditiously. 

Thanks to ongoing research efforts, doctors are now able to categorize cancer by some genomic changes in your DNA. This has altered the approach to treatment. Scientists have learned that some cancer types respond better to certain treatments and respond more poorly to others. Your colon or rectal tumor might not respond to the same treatment that other colorectal cancer patients receive, depending on the genomic changes (the biomarkers) in your tumor.

Knowing your biomarkers can help your doctors identify YOUR best treatment options and help you make well-informed decisions about how your cancer will be treated. Knowing your biomarkers will allow you to be your own best advocate.

Choosing your course of treatment based on the specific genomic changes of your cancer (what we refer to as biomarkers) will help your team deliver specific care that will be the most beneficial with the least amount of side effects. It will empower you to be an informed partner with your doctor in your cancer care.

Terms to Know

  • Wild-Type – no mutation in the biomarker
  • DNA Sequence Mutation – an alteration in the biomarker DNA sequence
  • First-Line Treatment – the initial (first) treatment for a cancer patient that is accepted by the medical community as the best option
  • Recurrence – the return of cancer after a period of remission (or after you’ve been declared no evidence of disease [NED])
  • Stage III – cancer that has spread to lymph nodes
  • Metastatic / Stage IV – cancer that spread beyond its original location in the colon or rectum and formed one or more tumors in other areas of the body, like the liver and/or lungs
  • Next Generation (Gen) Sequencing (NGS) – a technology that allows for multiple genes to be tested at the same time, at a fairly low cost
  • Pathologist – a doctor with training to identify diseases by looking at their cells.

Need help facilitating biomarker testing?

Fight CRC has partnered with Perthera to help facilitate the biomarker testing process. Perthera can help you and your doctor get your tumor tissue sample to a participating lab for testing. When the testing is completed, Perthera will provide you and your doctor with a comprehensive, easy-to-read report about your tumor. Their AI-based system will provide a list of ranked therapeutic options, which will include any appropriate clinical trials. If you have had biomarker testing completed in the last 12 months, Perthera can also analyze these results for appropriate therapeutic options including clinical trials.


What Are Biomarkers Used For?

Types of BiomarkersWhat They’re Used For
Diagnostic BiomarkersHelp identify the type of cancer you have
Prognostic BiomarkersUsed to learn about the estimated course of cancer if it goes without treatment by identifying how well-functioning a cell is, or if it is not functioning
Predictive BiomarkersUsed to identify the best available treatment by predicting whether or not the body will respond to a specific treatment. This is the type of biomarker that is discussed when it comes to treatment decision-making.
Pharmacodynamic BiomarkersHelp with treatment dosing decisions
Recurrence BiomarkersUsed to monitor if the cancer is coming back after it has been treated

When Should I Get My Tumor Tested?

Ideally, biomarker testing should be done before you start treatment. Biomarker testing should happen as close to your diagnosis as possible, before selecting a treatment plan. If you begin receiving a treatment before knowing your tumor type, this may exclude you from future treatment options, including some clinical trials. Take the time to talk to your doctor about tumor testing before making treatment decisions.

If you’ve already started treatment prior to tumor testing, it is recommended that you still receive the testing (it could affect your current treatment plan). The hospital where you had surgery most likely retained some of your tumor tissue. Contact your surgeon and connect them with your oncology team to learn more about how to get your sample sent to a pathologist for testing. If your tumor tissue was not saved, ask your doctor about the best way to move forward with biomarker testing.

Types of Biomarker Tests

Biomarker tests are performed on tumor biopsies to identify gene mutations, also known as biomarkers. After the biopsy is collected, it will be analyzed by a pathologist. A pathologist is a scientist who inspects laboratory samples of body tissue while studying the causes and effects of diseases. The pathologist will provide a report to your doctor on what was discovered about your tumor.

There are many types of biomarker tests that can help select cancer treatment. Most biomarker tests used to select cancer treatment look for genetic markers. But some look for proteins or other kinds of markers. Some tests check for a single biomarker. Others check for many biomarkers at the same time and may be called multigene tests or panel tests. 

Some tests, called whole-exome sequencing, look at all the genes in your cancer. Others, called whole-genome sequencing, look at all the DNA (both genes and outside of genes) in your cancer. 

Still other biomarker tests look at the number of genetic changes in your cancer (what’s known as tumor-mutational burden). This information can help figure out if a type of immunotherapy known as immune-checkpoint inhibitors may work for you.

Liquid Biopsy

A sample of blood that pathologists use to look for DNA from tumor cells or tumor cells in the blood. Pathologists are looking for circulating tumor DNA (ctDNA) and/or circulating tumor cells (CTCs).

There are two liquid biopsy tests approved by the Food and Drug Administration (FDA), called Guardant360 CDx and FoundationOne Liquid CDx.

Tumor Biopsy

A sample of cells or tissues from the tumor to be examined by a pathologist. There are incisional biopsies, where only a sample of tissue is removed; and excisional biopsies, where the entire tumor is removed.

Biomarker testing is NOT the same as genetic testing.

Types of Biomarkers in Colon and Rectal Cancers

KRAS

KRAS plays an important role in driving colorectal cancer cells to grow and divide. It is part of a pathway in tumor cells that can be triggered by activation of a receptor (think of an electrical socket) present on the surface of tumor cells. In this pathway, the receptor is known as the epidermal growth factor receptor (EGFR). If a biomarker test indicated a tumor has a KRAS mutation, then EGFR inhibitors (drugs that target EGFR) may NOT be beneficial because the receptor (think of the switch) on the cell wall, is permanently in the on position and cannot be turned off by available drugs. EGFR inhibitors include cetuximab (Erbitux) and panitumumab (Vectibix), and these are not generally used to treat people when their tumor is found to have a KRAS mutation.

KRAS testing is typically recommended for stage IV patients and at time of recurrence for any stage patient whose cancer recurs. There is currently no role for testing in stage I, II, or III CRC.

Biomarker-Recommendation Chart

NRAS

NRAS plays an important role in instructing colorectal cancer cells to grow and divide as part of the epidermal growth factor receptor (EGFR) process and has a similar function to KRAS. If a biomarker test indicates an NRAS mutation, EGFR inhibitors (drugs that target EGFR) may NOT be beneficial and may make the tumor grow faster. EGFR inhibitors include cetuximab (Erbitux) and panitumumab (Vectibix).

NRAS testing is typically recommended for stage IV patients and at time of recurrence for any stage patient whose cancer recurs. There is currently no role for testing in stage I, II, or III CRC.

KRAS wild-type

KRAS wild-type means a tumor does not have a KRAS mutation. Patients whose test results show KRAS wild-type may respond well to certain treatment plans that include EGFR inhibitors.

KRAS testing is typically recommended for stage IV patients and stage III recurrence.

NRAS wild-type

NRAS wild-type means a tumor does not have an NRAS mutation. Patients who are NRAS wild-type may respond well to certain treatment plans that include EGFR inhibitors.

NRAS testing is typically recommended for stage IV patients and stage III recurrence.

BRAF

BRAF is a gene that signals cells to divide. Approximately 1% of patients with mCRC have a tumor with a BRAF mutation other than BRAF V600E. The prognosis of the mCRC patients with tumors that harbor a BRAF mutation other than the specific V600e mutation is better than that of the average person with mCRC. Patients with a BRAF mutation may not respond to EGFR-inhibitor drugs, such as cetuximab (Erbitux) and panitumumab (Vectibix).

If a BRAF mutation is detected, there may be a poorer prognosis with the use of standard chemotherapy regimens; therefore, clinical trials may be a good option. Additionally, research is showing that emerging subgroups of the BRAF mutation can affect prognosis.

BRAF testing is typically recommended for stage IV patients. This test can be done at the same time as KRAS and NRAS testing. BRAF testing is also often done on stage II patients whose tumors are found to be MSI-H as a way to help determine if the MSI-H status of the tumor is inherited or acquired. There are specific drugs and drug combinations, which target BRAF mutations.

Tumor pie chart

BRAF V600E

The presence of a BRAF V600e mutation suggests a particularly aggressive cancer that requires aggressive treatment. It is present in approximately 15% of patients with early-stage CRC and 6% of those with mCRC (mCRC).  Approximately 20% of patients with BRAF V600E–mutated mCRC also have MSI. Just like any other patients with MSI, these patients can respond to checkpoint inhibitors such as nivolumab and pembrolizumab. Additionally, vemurafenib is a drug that was included as a therapeutic option to treat BRAF V600e CRC in the 2018 version of the National Comprehensive Cancer Network’s Clinical Practice Guideline.

Current research is exploring combinations of immunotherapy and targeted therapy in patients with BRAF-mutated MSS CRC.

PIK3CA

The PI3 kinase (PIK3CA) pathway contains genes needed for multiple cell functions including cell growth (proliferation) and survival. Testing for this mutation is not standard practice, per guidelines as of October 2017.

Patients with stage II or III (limited stage CRC) whose tumors harbor a PIK3CA mutation may benefit from aspirin therapy after surgical resection, as it can help decrease the risk of recurrent CRC.

Currently there are no recommendations for routine testing of PIK3CA, though testing may be suggested for stage I, II, and III patients. It is noteworthy that although PIK3CA inhibitor therapies have been approved for treatment of other types of cancer, this has not yet happened for colorectal cancer.

MSI-High

MSI-H, also referred to as “mismatch repair deficient” or “dMMR”, results when genes that regulate DNA (called Mismatch Repair Genes) don’t work correctly. Mismatch Repair Genes (MMR) work like genetic “spell checkers” by correcting errors that occur in the coding of DNA as cells divide. They work in a similar way to “spell checkers” that correct typos in a word processing program on a computer. When MMR genes stop functioning at their highest potential, areas of DNA could start to become unstable due to the errors leading to the development of a number of kinds of cancers including CRC.

An MSI screening test looks for changes in the DNA sequence between normal tissue and tumor tissue and can identify whether or not there is a high amount of instability. If this instability is present, those tumors are classified as MSI-High. Similarly, a dMMR test looks for the presence or absence of the mismatch repair proteins on special stains done on the tumor sample. In simple terms, MSI testing looks to see if the DNA is mutated and is not making the mismatch repair proteins (the “spell checkers”), and MMR staining looks to see if the MMR proteins are actually present in white blood cells that are present in blood. Both tests achieve the same result to determine whether the tumor is MSI-H, also called dMMR.

MSI-H or dMMR is found in about 15% of colon tumors. About a quarter of MSI-H or dMMR tumors are associated with the hereditary syndrome, Lynch syndrome, though many MSI-High tumors are sporadic (not due to a hereditary syndrome).

While 15% of all CRC tumors are MSI-high or dMMR, only about 4% of patients with mCRC will have MSI or dMMR tumors. Those who do have MSI-H or dMMR metastatic tumors are the small subset of patients who are likely to benefit from treatment with currently available immune checkpoint inhibitors.

MSI or MMR testing is recommended for ALL colorectal cancer patients. Talk to your surgeon or oncologist about MSI or MMR testing.

CEA

CEA (or Carcinoembryonic Antigen) is a protein that is commonly elevated in CRC patients and is present in low levels in healthy people or modestly elevated levels in individuals with inflammation of the colon. In patients with mCRC, higher levels of CEA may indicate that cancer is growing while lower levels may indicate that treatment is working. Not all patients with CRC will have an elevated CEA.

Sidedness

Research suggests there may be a difference in biology, depending on the side of the colon that cancer originates (right versus left). Based on the research, patients with right-sided tumors may not have the same results and success rates if EGFR-inhibitor therapy is used as the first line of treatment as compared to patients with left-sided tumors. In those patients the targeted agent bevacizumab is often recommended in addition to standard chemotherapy.

HER2

HER2 (or human epidermal growth factor receptor 2) is being studied as a possible pathway that can be targeted with available drugs, which can be overactive in patients with KRAS wild-type tumors. In approximately 5% of KRAS non-mutated (wild-type) cancers, HER2 is amplified. Combination therapies including trastuzumab and lapatinib have been tested with these patients in phase II studies, resulting in a 35% overall response rate and a median time to progression of about five and a half months.

TRK Fusions

Tropomyosin Receptor Kinase (TRK) fusions are genetic abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) become connected (fused) to another gene that is not related (e.g., ETV6, LMNA, TPM3). This connection leads to TRK signaling that is uncontrolled and could lead to cancer. TRK fusions are rare; however, when they are present, there could be an option for a clinical trial for treatments targeting TRK inhibition. Additionally, new drugs, which target NTRK fusion-positive mCRC have recently been approved, including entrectinib and larotrectinib. These have been approved for metastatic solid tumors that have either progressed following prior therapies or as initial therapy when there are no acceptable standard therapies.

Pathways

You may hear your treatment team refer to pathways or signaling pathways when talking about biomarkers or your treatment plan.

These are a type of biomarker that determine the behavior of cancer cells. The PD-1/PD-L1 and Wnt pathways are commonly discussed in colorectal cancer research and are targets for some treatments.

PD-L1 PATHWAY

PD-L1 is an immunosuppressive driver, meaning that it stops the immune system from functioning at its optimal level. Some cells within the body, called T-cells, have receptors on them which make sure that abnormal or mutated cells don’t multiply.

Think of these T-cells as security guards and PD-L1 as a disguise on abnormal cells. With the presence of PD-L1, the T-cell receptors are unable to see that the mutated cells are mutated due to the PD-L1 “disguise”; therefore, the mutated cells get through the security guards and are able to multiply, becoming cancer. Nearly half of all cancers have the PD-L1 biomarker. Therefore, many researchers are using the presence of PD-L1 as a pathway to fight cancer.

 

TUMOR MUTATIONAL BURDEN (TMB)

TMB is a biomarker made up of the total number of mutations per coding area of a tumor genome. Some researchers are now using it to identify which patients would benefit from the checkpoint inhibitor therapy (like ones that target PD-1/PD-L1). A high level of TMB may indicate that you would benefit from this type of treatment.

WNT PATHWAY

The Wnt pathway is a complex pathway responsible for stability and is often highly mutated in colorectal cancer patients. When not functioning properly, the pathway could lead to mutations in adenomatous polyposis coli (APC) genes in the body, which are found in most of all sporadic colorectal cancer in addition to familial adenomatous polyposis (FAP — a heritable syndrome. To learn more, download our Genetics Mini Magazine). Targeting the Wnt pathway, especially through the use of combination therapies, is something researchers are studying for more effective treatment plans.

Biomarker Resources

Stories

Frequently Asked Questions

As a stage I or II CRC patient, what are the current recommendations for biomarker testing as it relates to my treatment decision-making?

Currently, only MSI testing is recommended. However, it is strongly recommended that all CRC patients learn about their family health history of colon and rectal cancers. Depending on the history, patients will be referred to genetic counseling to learn if they are at a higher risk for developing other cancers or if their family members are also at a higher risk.

When should I talk to my doctor about biomarkers?

Talk with your healthcare team about tumor biomarker tests immediately after your diagnosis. If you are already on treatment and are unsure whether or not you have received biomarker testing, ask your treatment team.

What will my results look like?

Your test results will show whether your tumor has a mutation (positive test results) or if it is wild-type (negative test results; no mutation detected). Your doctor will review your test results with you and discuss how they will affect your treatment decisions. If you would like a copy of your test results, be sure to request them. Finally, if you have questions for your treatment team, be sure to ask!

Is it possible to have both KRAS and BRAF mutations?

It would be extremely rare. If you have a BRAF-mutant tumor, you most likely will not be KRAS mutant, and vice versa.

Will I need another biopsy to test my tumor?

No. When you had surgery, some of your tumor tissue was removed and stored at the hospital. Your doctor can arrange for your tissue to be sent to a lab. Results will go to your doctor. The tissue sample tested can be from your original cancer in your colon or rectum, or from a metastatic tumor that has spread.

Why haven’t I heard about this before?

Your provider should be discussing biomarker testing with you. If they haven’t, be sure to advocate for your care and start the discussion. Our biomarker testing discussion guide is a great place to start.

What are the downsides of biomarker testing?

There are multiple biomarkers that have been scientifically shown to be meaningful in colorectal cancer. While more and more biomarkers are being studied, not all are shown to have clinical relevance or benefit the patient’s treatment decision-making.

I’ve had genetic testing. Does this mean I’ve had biomarker testing?

Genetic testing is a type of biomarker testing, but does not ensure that you have received all the biomarker tests necessary to make an informed treatment decision.

I’ve been told I have Lynch syndrome. Does this mean I’ve had biomarker testing?

This means that you have received MSI testing. To learn if you have received testing for additional biomarkers, you will need to check with your doctor.

Will I get to see my test results?

Your doctor will likely explain the results of your biomarker test with you when they come in. If they don’t, just ask! Additionally, if you’d like to keep a copy of the report for your records, don’t hesitate to ask for one. Make sure you clearly understand the results, so that you can participate in shared decision-making for your treatment plan.

Will my insurance cover biomarker testing?

If you are participating in a clinical trial, the trial may cover the cost of biomarker testing. Private individual or employer-sponsored health insurers will usually cover biomarker tests when they are “medically necessary.”

Is there financial assistance for biomarker testing?

Some people may avoid testing due to perceived financial burden. Luckily, many labs offer patient assistance for out-of-pocket costs, and insurance companies may cover costs as well. Talk to your social worker and call your insurance provider to learn more.

Who makes the guidelines?

In May 2017, four professional groups published evidence-based guidelines for biomarker testing for colorectal cancer. The Guideline, titled Molecular Biomarkers for the Evaluation of Colorectal Cancer Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology provides recommendations for mismatch repair status testing. RAS mutation testing for patients being considered for anti-EGFR therapy, and BRAF testing for colorectal cancer patients, in addition to other recommendations and expert consensus opinions for the implementation of biomarker testing. As research continues to evolve, guidelines and recommendations will also likely change to reflect the most relevant and meaningful research.

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