What are biomarkers?
When discussing testing and surveillance, you’ll likely hear people talk about biomarkers. But what are they?
In the context of colorectal cancer, biomarkers are typically proteins found in and released by the tumor or metastases. They can be detected using blood, other bodily fluids, or tissues.
What information can biomarker testing provide?
Biomarker testing can be prognostic or predictive. What does that mean?
- Prognostic biomarkers provide information on the overall cancer outcome, regardless of specific therapy
- Predictive biomarkers provide information on the effects of a potential intervention or treatment
Biomarker testing can provide personalized information, which can be used to:
- Gain a better understanding of the prognosis of your cancer
- Help predict how your cancer may or may not respond to a particular treatment
- Guide treatment decisions
- Predict potential severe side effects (toxicities) of treatment
- Monitor cancer for recurrence
Still a bit confused? Take a look at this video from our friends at the Cholangiocarcinoma Foundation:
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What are some common biomarkers?
MSS/MSI-H
All colorectal cancer patients should have their tumors tested for MSS/MSI-H status. This test is usually done on tumor tissue obtained from a biopsy during a colonoscopy, or from tissue removed during surgery. Approximately 85% of colorectal cancers are MSS, and about 15% are MSI-H. 96% of metastatic CRC is MSS, while 4% is MSI-H.
Even though MSI-H is relatively uncommon in stage IV CRC, it’s important to know this about your tumor, because patients with MSI-H CRC qualify for immunotherapy — which can result in a cure for a subset of these patients.
MSI-H tumors are much rarer in rectal cancer (found in 0.5-1% of patients). However, if the tumor is MSI-H, these patients are eligible for first-line immunotherapy trials.
For more information on MSS/MSI-H, click here.
RAS
All patients who are diagnosed with stage IV metastatic CRC should have their tumor tested for RAS status. There are three different RAS family members (KRAS, NRAS and HRAS) that can be mutated in colorectal cancer. However, HRAS is very rarely mutated. Approximately 40% of CRC patients have tumor mutations in the KRAS gene, and about 5% have mutations in the NRAS gene. If you do not have a RAS mutation, your report may say your tumor is “wild type” or “WT” — meaning your gene is normal and unmutated.
Not only is RAS mutation status important, but the specific variant should be identified, because treatment can be targeted to specific variants. Some common KRAS mutation variants are: KRAS G12C, G12D, G13C and AI46T.
For stage IV patients, your tumors’ RAS status is important for treatment decisions. Tumors with RAS mutations do not respond well to EGFR inhibitors, such as panitumumab and cetuximab, so if you have one of these mutations, you are not eligible to receive these drugs.
RAS mutations can also be acquired over time as a resistence mechanism to therapies such as EGFR inhibitors — so repeating RAS testing at disease progression or recurrence can be useful.
There are also clinical trials targeting specific RAS mutation variants, such as KRAS G12C, so knowing your RAS status can help you figure out which clinical trials you qualify for.Â
Want to learn more about RAS mutations?
Join one of our COLONTOWN support groups:
- Check out the RAS Clinic to learn about patient and caregiver experiences about dealing with RAS-mutated CRC
Want to join? Fill out the registration form here.
BRAF
All patients diagnosed with colorectal cancer should have their tumors tested for BRAF status. BRAF mutations are found in 10-15% of CRC. If you do not have a BRAF mutation, your report may say your tumor is “wild type” or “WT” — meaning your gene is normal and unmutated.
One particular mutation — BRAF V600E in MSS CRC — can cause a much faster-growing cancer. Tumors with BRAF V600E mutations generally do not respond to EGFR inhibitors, such as panitumumab and cetuximab, alone or in combination with chemotherapy. However, these patients do respond to what is called a “Beacon doublet,” which combines an EGFR inhibitor (panitumumab or cetuximab) with a BRAF inhibitor (encorafenib).
Want to learn more about BRAF mutations?
Join one of our COLONTOWN support groups:
- Check out the BRAF Clinic to learn about patient and caregiver experiences about dealing with BRAF-mutated CRC
Want to join? Fill out the registration form here.
In this video, Dr. Kopetz gives an overview of the treatment options available for patients with BRAF mutations:
HER2/ERBB2
HER2 (also called ERBB2) amplifications/mutations are present in about 8% of rectal cancer and 3% of colon cancer, so it can be useful to test all CRC patients for HER2 gene alterations. HER2 gene alterations can also be acquired over time as a resistance mechanism to therapies such as EGFR inhibitors — so repeating HER2 testing at disease progression or recurrence can be useful.
If you have a HER2 amplification, there are drug treatments you qualify for. These drugs include trastuzumab with pertuzumab or lapatinib, either alone or alongside chemotherapy. In addition, you may be eligible for first-line clinical trials — but these trials are only available for people who have not started chemotherapy yet. So it’s very important that you ask your oncologist about HER2/ERBB2 testing and trials.
Want to learn more about HER2 mutations?
Join one of our COLONTOWN support groups:
- Check out the HER2 Clinic to learn about patient and caregiver experiences about dealing with HER2-mutated CRC
Want to join? Fill out the registration form here.
TMB
Tumor mutational burden (TMB) is a measure of gene mutations found in the tumor DNA. It is expressed as number/megabase (Mb). In general, MSI-H tumors have a higher TMB (greater than 20/Mb), while MSS CRC has a much lower TMB on average (around 4-6/Mb).
Many patients with MSI-H CRC are eligible for immunotherapy. Very rarely, MSS CRC patients with POLE or POLD mutations may have a very high TMB (greater than 100/Mb), and these patients are also likely to respond to immunotherapy. More commonly, a small subset of MSS CRC patients may have a TMB closer to 15/Mb, and these patients may respond to combination therapies with immunotherapy. Therefore it’s important for all patients with metastatic CRC to learn the TMB of their tumor and discuss options with their care team.
TMB testing is part of tumor genomic testing, and a variety of panels that include TMB are now available. TMB is usually determined from testing tumor tissue. This is called tissue TMB. TMB can also be calculated using a blood sample, and this is called plasma or blood TMB. The numbers above are tissue TMB numbers, and are not directly comparable to plasma TMB numbers.
More information about tumor genomic testing can be found in the Diagnostic & Surveillance Testing Learning Center.
CEA
Carcinoembryonic antigen (CEA) is a common tumor marker found in the blood. Testing for CEA levels can help determine if your cancer is growing, or if the cancer has returned. It’s usually included in regular blood tests CRC patients take during treatment and surveillance.
It’s important to note that not all colorectal cancers will express high levels of CEA, and it may not be a useful biomarker for all patients. Your cancer may be visible through scans, but your CEA levels may be within normal ranges. In these cases, other markers such as CA 19-9 (used less commonly for CRC) or circulating tumor DNA (ctDNA) may be additionally used to keep track of your cancer.
Individual CEA levels can vary remarkably between people. All it may reflect is whether or not your tumor is a high CEA expresser. For example, one person with stage IV CRC can have a CEA value of 8, while another patient with stage IV CRC may have a CEA of over 500 — or 50,000!
That’s why it’s important to notice the trend of CEA changes — how your CEA values change from diagnosis to after surgery to recurrence to stable disease. This can give you much more valuable information than a one-time number. Simple graphic tools can be used to figure out this trend, and they’re often available on online patient portals.
CA 19-9
CA 19-9 is not a commonly used biomarker for colorectal cancer patients, but it can be useful for people who have normal CEA at diagnosis. CA 19-9 is sometimes elevated with peritoneal metastases, and may be an additional biomarker for patients with BRAF mutations. Since this biomarker is not so commonly used in CRC monitoring, it’s a good idea to discuss whether or not it might be useful for you with your care team.
Sidedness
Sidedness is considered as a newer biomarker for CRC. Colorectal cancer that arises from the left and right sides of the large intestine have differences in their molecular makeup — which makes them more or less responsive to certain drug combinations.
Broadly, tumors in the cecum, ascending colon and transverse colon are referred to as right-sided CRC, while tumors in the descending colon, sigmoid colon, and rectum are referred to as left-sided CRC.Â
Approximately 70% of tumors are located on the left side, and 10% are on the right. EGFR inhibitors (panitumumab and cetuximab) seem to be more effective in left-sided tumors. Right-sided tumors are more likely to be MSI-H, and patients with MSI-H tumors may qualify for immunotherapy.
ctDNA
Circulating tumor DNA (ctDNA) is a very recently identified biomarker that has attracted the attention of patients — and is the topic of discussion in many CRC support groups since 2019!
Simply put, ctDNA is tumor trash in the blood stream. If there is a tumor that’s growing in the body, the cells of the tumor turn over continuously. This means that at any given time in a growing tumor, more cells are dividing than dying. In a shrinking tumor, in contrast, more cells are dying than dividing. Dead cells shed pieces of their DNA into the blood stream. Tumor cells have mutated DNA, and ctDNA tests look for this mutated tumor DNA in the blood stream.
ctDNA can be thought of as an “ultra sensitive” CEA test, and can give you more information about cancer in your body. Since this is a very new biomarker, there are many uncertainties about its use — and it’s not widely accepted in the US or other countries. Whether ctDNA is useful for you is something to discuss with your care team.
The Diagnostic and Surveillance Test Learning Center has a lot of information on ctDNA testing and covers 3 commonly used tests. Dr. Stacey Cohen talks about the use of ctDNA in CRC in a very informative talk available in the Lecture Hall.Â
Treatment toxicity biomarkers
Not everyone reacts the same way to medications. Some biomarker tests can determine how your body breaks down (metabolizes) certain chemo drugs. These tests can help your doctor figure out the best treatment plan for you. Your doctor may call this pharmacogenomic or PGx testing. Note that PGx tests are testing your body’s genes, not the tumor’s genes!
There are two main gene tests for patients taking chemotherapy for CRC. These tests are widely available but not usually done in the US, unless a patient develops severe side effects from treatment (although this standard is evolving). Though it’s rare, reactions to treatment can be serious and it’s important to know what to look for and report. We’ll go over them below:
DPYD
The DPYD gene tells your body to make something called the DPD enzyme. This enzyme helps break down the drug 5FU (a major component of chemotherapy, the second F in FOLFOX) and the related drug capecitabine (the C in CAPOX). If your body has trouble breaking down 5FU, the drug stays in the body for a longer time and can result in severe side effects and toxicity.
The FDA now states that doctors should test for DPYD when prescribing chemo regimens containing 5FU (FOLFOX, CAPOX, FOLFIRI, CAPIRI or FOLFOXIRI). You should ask about taking the test before starting chemo. If your oncologist doesn’t recommend the test at that time, you should tell them you want to get tested before starting chemo. The test is not 100% accurate (see DPYD testing and ethnicity box below), so you should ask about how you should report potential severe side effects and how your team will address them.
All patients that experience specific side effects like uncontrolled diarrhea, chest pain or discomfort, or dehydration after the first one or two cycles of chemo should request a test for DPYD deficiency to rule out this rare condition.Â
Complete DPYD deficiency is relatively uncommon (about 1 in 500 people) but it can be life threatening if not managed immediately. Partial DPYD deficiencies are much more common (5-7% of people), can also lead to severe toxicity, and can be identified via pharmacogenomic testing.Â
If your team suspects or finds out from testing that you have a partial DPYD deficiency, they’ll likely manage it with a reduced dose of 5FU and extra fluids. Always report your side effects promptly to your care team, so they can make sure your treatment is most appropriate — and most comfortable — for you!
Did you know that ethnicity is important for DPYD testing?
There is a lot of genetic diversity around the world, but often this genetic diversity is not taken into consideration when developing genetic tests. For example, DPYD tests were developed on genetic information from primarily white American people. If you are of a different ethnicity or background (South Asian, Latin American, Black, etc) make sure that you and your doctor consider this while reviewing your test results. Here’s what you should know.
If your test is positive: This is useful information! Discuss next steps with your doctor about what this might mean for you.
If your test is negative: This does not necessarily rule out DPYD mutations. It confirms that you don’t have the DPYD variants that the test checks for, but you may have other variants not checked for in this test.Â
What to do next: If you’re still having symptoms that align with DPYD deficiency, you can ask for DPYD gene sequencing that identifies all potential variants. Regardless of your genetics, if you are experiencing severe symptoms you should talk with your doctor about ways of managing your side effects, including reducing or discontinuing treatment in very severe cases.
For more information on DPYD:
Head to test4dpd.org
UGT1A1
The UGT1A1 gene tells your body to make an enzyme that is important in breaking down the chemotherapy drug irinotecan (the IRI in FOLFIRI, CAPIRI or FOLFOXIRI). Gilbert’s syndrome is a condition associated with variants of the UGT1A1 gene, and is present in 3-7% of the US population.
If you’re not taking irinotecan, there are no negative effects from Gilbert’s syndrome in everyday life. Actually, most people with Gilbert’s Syndrome don’t even know they have it!
Routine testing for UGT1A1 variants are not done in the US. When patients experience increased toxicity and side effects with chemotherapy containing irinotecan — such as FOLFIRI or FOLFOXIRI — irinotecan doses are often reduced.
Gilbert’s Syndrome and bilirubin
If you have Gilbert’s Syndrome, your liver also has trouble breaking down bilirubin. While this is not dangerous on its own, it’s something you should keep something in mind if your bilirubin is too high for treatment or when looking for clinical trials. Some trials will have a different bilirubin limit for people with Gilbert’s Syndrome, affecting whether or not you’re eligible for a trial. If you have more questions about this, please speak to your doctor.
For more information on UGT1A
Head to knowyourbiomarker.org
Rare yet important mutations
While the above mutations are most common, there are a few other tumor mutations that are important for stage IV patients to know. These are very rare for CRC, but there may be effective treatments in later lines of therapy for these patients. These mutations are commonly included in multi-gene testing panels, like next-generation sequencing (NGS) panels — so these mutations will not likely be tested for individually. If your tumor does not have these mutations, you may not see them on your results. However, you can confirm with your doctor, or look for a list of “mutations tested” in your NGS report to confirm they were included in the analysis. If they weren’t there are additional kinds of tests that your oncologist can order that can detect these mutations.
The following mutations or fusions are typically found in less than 1% of CRC, and most often occur in tumors that are also MSI-H. For MSI-H patients, knowing the status of these mutations is critical, especially if immunotherapy isn’t effective. For MSS patients, it’s very rare to have these mutations — but when they do exist, there may be additional treatment options available to patients.
NTRK
NTRK fusions are found very rarely in colorectal cancer, in less than 1% of patients. Usually, they occur in MSI-H tumors. There are very effective drugs available that target NTRK fusions, such as larotrectinib and entrectinib. These drugs can result in a cure for patients with NTRK fusions — therefore it’s important that metastatic CRC patients, especially those who have MSI-H tumors, get tested for NTRK fusions.
It’s important to note that NTRK mutations are different than NTRK fusions, and the drugs mentioned above may not work against NTRK mutations.
RET fusions
There is a drug that effectively targets RET fusions called selpercatinib. It’s important to note that RET mutations are different than RET fusions, and the drug mentioned above is only indicated for RET fusions.
POLE/POLD
POLE/POLD mutations are often associated with a higher tumor mutation burden. While there aren’t specific targeted drugs for these mutations, immunotherapy agents can be effective at treating these tumors. If you are an MSS patient with one of these mutations, discuss whether immunotherapy might be an option for you with your oncologist.
Want to learn more?
This table from the Global Colon Cancer Association gives a good overview of what we currently know about CRC biomarkers, who should get tested, as well as what the consequences are for treatment. It goes over all the biomarkers listed here, as well as some of the less common and less actionable biomarkers such as P1K3CA. Click here for a full-sized PDF version, which you can download!
So what does all of this mean for treatment?
Knowing your biomarkers, particularly if you are stage IV, is really important! They give you and your team useful information which can help determine which treatments will be most effective for you. They can also give you information that can help you figure out if you qualify for clinical trials.
In this video, Dr. Kim and Dr. Kopetz discuss the importance of biomarker testing for stage IV patients:
Unfortunately, data suggests not all stage IV patients receive the recommended biomarker testing.
To help, we’ve put together a biomarker worksheet that you can print out and give to your oncologist to fill out for you!
Want to learn more about biomarkers and what they mean for treatment?
Join one of our COLONTOWN support groups:
- In Tom & Con’s BRAF + Clinic, you can chat with other patients who have the BRAF mutation.
- In Tom’s RAS Clinic, you can ask all your questions about treatment options for patients with the RAS mutation.
- Tom’s HER2 Clinic is for patients with HER2 mutation/amplification.
- On the Right Side is a group for patients with right-sided tumors to discuss experiences and treatment options.
Want to join? Fill out the registration form here.
Video: Simple guide to biomarker testing
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Last updated: January 5, 2023