The Importance of Biomarkers in Colorectal Cancer Treatment

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An exciting colon and rectal (colorectal) cancer study presented during the 2022 ASCO Annual Meeting – simultaneously published in The New England Journal of Medicine – indirectly brought worthy attention to the importance of biomarker testing. We recently spoke with Richard Goldberg, MD, professor emeritus at West Virginia University and a Fight CRC Board member, to learn more about the importance of biomarkers and biomarker testing.

Richard M. Goldberg, MD

We can’t possibly understand all the implications, but this is an exciting time to see the progress we are making with biomarkers and potential treatment options for colorectal cancer.

15 Things You Need to Know About Biomarkers and CEA

Table of Contents:

1. What are biomarkers and CEA? And why are they both so important?

Biomarkers have a broad definition, but when talking about cancer, biomarkers are indicators of disease. They help us create targeted therapies that are more specific and selective in the cells that they kill, as opposed to chemotherapy which kills lots of cancer cells – but it also can kill lots of healthy cells, too.  Carcinoembryonic antigen (CEA) tests have been used for decades as a tool to detect colorectal and gastrointestinal cancers and test the level of CEA in the blood. Although present in very small amounts in healthy people, it can be extremely elevated in those with inflammatory bowel disease (IBD) or colorectal cancer.  

CEA levels correlate with disease in a person’s body: If a person is diagnosed with cancer and has a CEA level of 50, then begins chemotherapy or targeted therapy and their CEA level drops significantly, it means the treatment is working – which is good news.

If a person’s CEA level continues to rise even after treatment, this is a sign that current treatment isn’t working, and it’s time to change to a different option.

With the advent of multigene testing – testing done on a person’s own DNA or tumor DNA – a lot of different biomarkers have been identified. Multigene testing looks at hundreds of abnormalities that may be found in DNA.

2. Biomarkers and biomarker testing explained in more detail

One common cause of abnormalities in DNA seen in cancer cells is called microsatellite instability (MSI). The basics: Cancer is characterized by cells that divide more often and uncontrollably compared to normal cells. Any time a cell divides, the DNA in the cell has to be copied so two new cells can be made from the original cell’s DNA. In tumors with MSI, the copied DNA has mistakes that occur when the DNA is copied that normally would be repaired. The process resembles the process by which a spell checker program corrects misspelled words in a document. In cells with MSI these errors are not repaired and this can lead to cancer. In people with MSI, mutations may not be corrected as the cells divide, leading to “instability.” 

People who have Lynch syndrome have MSI. Biomarker testing is important to identify these patients and which of their family members have Lynch syndrome. Each close family member of a patient who has been found to have the syndrome has a 50% chance of also having  the Lynch syndrome. Those family members with Lynch Syndrome need extra cancer screening tests and also can reduce their risk of cancer by taking aspirin.

Patients whose tumors show MSI have different responses to chemotherapy and immunotherapy than those without MSI. For patients with Lynch syndrome, some types of chemotherapy are less likely to work. The positive side of Lynch syndrome is that patients with MSI tumors are more likely to respond to immunotherapy approved for treatment of colorectal cancer and other cancers. The immunotherapy agents can be exceptionally effective, as we saw recently with the rectal cancer study at ASCO 2022, which means patients who have MSI have the opportunity to take advantage of this therapy.

Unfortunately, these immunotherapies are not helpful or successful in patients whose tumors do not have the MSI biomarker.

There are many other biomarkers that we can look at by doing a genetic analysis on the tumor’s DNA to determine which genetic changes are driving the growth of the cancer cells.

For example, BRAF-600e is a protein that is abnormal in about 15% of patients with colorectal cancers, and the formation and growth of their tumor cells are driven by that mutation. Unfortunately, those tumors are resistant to a number of drugs that we routinely use for treating colorectal cancer. Finding that a tumor has this gene can give a treatment team notice of which treatments could and which drugs likely will not work for certain patients with this biomarker, and biomarker testing allowed doctors to discover the medicine encorafenib, which targets BRAF mutations, and was effective in treating those patients.

The important concept with biomarkers and biomarker testing is the more we can find out about a person’s tumor, the better we can anticipate whether specific drugs are likely to work and sometimes that a tumor is likely to be resistant to a particular drug. In some cases a drug that helps 15% of the colorectal cancer patients may not be useful to prescribe to treat the other 85%.

RAS is more common than BRAF-600e. Patients may have mutations in NRAS or KRAS. About 50% of the colorectal cancer patients have one of the RAS mutations. Tumors with a RAS mutation are resistant to certain targeted drugs, such as Cetuximab and Panitumumab. These two drugs cause side effects but do not benefit this group of patients and are not prescribed as a part of their treatment.

There are also some rare mutations. Under a microscope, all colorectal cancers look generally the same and most are classified as moderately differentiated adenocarcinomas. The appearance of the tumor under the microscope cannot tell the medical team anything about its likelihood to respond to drug treatments. A genetic analysis of the tumor can help to determine what is driving tumor growth and how to kill those cancer cells. An example of a driver mutation is called an NTRK fusion. When a tumor has an NTRK fusion there are several drugs that are very specific and effective in treating such tumors, but this driver mutation only affects 2% of colorectal cancer patients.

“I didn't even know what it was. I believe the GI doc who did my colonoscopy ordered it when he took a biopsy. When I got into Moffitt, they looked up my records and mentioned it to me. That's when I learned I already had it done. I know I had it done when I was first diagnosed. Don't know much about it but do know it helps dictate the treatment options your oncologist will suggest with the best chances of working.”

Tim McDonald, stage IV survivor

3. What is the most important thing I need to know about each biomarker?

Rather than sort them out and explain each one, let’s put them in a basket and say the most important thing to know is that biomarkers and biomarker testing exist, and they provide information about how a tumor is likely to progress. For example, we know that when a patient’s tumor harbors a BRAF mutation, it has a poorer prognosis. We also know MSI-H tumors tend to have a better prognosis.

A patient’s treatment can be tailored to fit specific mutations they may have, and they can receive individualized treatment rather than the standard of care.

4. Are biomarkers found in the blood or tumor?

Biomarkers are found both in a patient’s blood and their tumor. For example, CEA is found in the blood, and the genomic abnormalities are found in the tumor. Sometimes, as in patients with Lynch syndrome, every cell in the patient’s body and in the tumor has the biomarker abnormality.  

5. If someone has genetic testing, and it shows their cancer has not developed because of an inherited syndrome, do they still need biomarker testing?

Yes! The interesting thing about cancer is that it happens because of mutations in DNA. As a tumor grows and is exposed to treatment, it continues to mutate and the mutations making it grow can change to avoid the effects of the treatment. 

Biomarker testing on a patient’s tumor, even one that hasn’t metastasized or spread, is important because the information provided can be helpful in knowing what treatment options may or may not work. If the disease is recurrent, tumor retesting may be necessary because the tumor may have become resistant to treatment that worked before or acquired a new susceptibility to the treatment.

6. Does insurance cover biomarker testing?

Unfortunately, this question doesn’t have a one-size-fits-all answer. For example, some states with expanded Medicaid provide the opportunity at the time of diagnosis to become insured if not already. Some private insurers will cover some or all of biomarker testing, also called genomic testing, which is different from germline genetic testing. Each patient should check with their insurance company and policy to see if your insurance covers biomarker testing.

The NCCN (National Comprehensive Cancer Network) provides a thorough guide for patients and providers, and is well-respected within the cancer community. The NCCN has endorsed biomarker testing for different cancers, and over time some insurance companies have been increasing coverage to include this testing. Some, but not all, insurers are guided by the endorsements of NCCN.

“I was diagnosed and cared for at a teaching hospital (OHSU in Portland). When I was diagnosed my oncologist said that there would be some basic biomarker testing, which helps guide treatment and to determine if I was a fit for a trial they were part of. I was also approached by the genetic research department to participate in testing as part of a study. I received a full report, which made little sense to me at the time because I had little context or explanation. I’ve learned a lot more through Colontown resources. I had no issues around comfort talking to my team. I’m in healthcare. I think it all happened so fast (I had colon surgery two weeks after diagnosis and was accepted into the trial within a month of diagnosis), and I was overwhelmed with information and my situation."

–Shanie Mason, stage IV survivor

7. What biomarkers are specific to colorectal cancer?

None of the biomarkers is specific to colorectal cancer alone. Biomarkers are drivers in other cancers and have commonalities and differences among cancers.

For example, in lung cancer, targeting tumors that harbor RAS mutations has proven to be more effective than it has been in targeting tumors with RAS mutations in colorectal cancer.

8. How many biomarker types are there?

There are many more biomarkers than we currently understand and comprehend because we are consistently learning so much about them.

As we look at colorectal cancer, approximately 30% of the cases will turn out to have a specific strategy driven by genomic testing, and that is terrific news.

Fight Colorectal Cancer advocates for physicians to take advantage of biomarker testing more often. Ideally all patients with colorectal cancer should have biomarker testing to determine Lynch syndrome or another cancer susceptibility syndrome that may be relevant to the tumor, and their family members’ history.

9. If my GI finds a tumor during my colonoscopy, will they automatically send a piece to get biomarker testing done?

No. This is not always done automatically. Remember, it’s important to talk with your insurer to see if they will cover biomarker testing. Biomarker testing is something a patient needs to ask about as some providers do that test automatically and others do not.

Fight CRC is dedicated to trying to change this because we see the value in the information that biomarkers and biomarker testing provides. We believe that the time has come in which all patients should have pieces of their tumor and, if abnormalities are identified to follow that by having their own DNA tested at diagnosis. It is also important to have biomarker testing to see if they have a cancer predisposition syndrome.

Ask your doctor about biomarkers and biomarker testing to determine your treatment course and to determine if you may have family history of Lynch syndrome.

10. If someone was diagnosed five years ago and did not know about biomarkers then, are they still able to request it be done now?

Yes. It is never too late to get biomarker testing done. I know a number of individuals who have had colorectal cancer, and some were diagnosed at a very early age. They may have been diagnosed decades ago, and they may have Lynch syndrome but didn’t have biomarker testing as an option at the time. If you have Lynch syndrome, you have always had it, and you always will. It doesn’t matter when you get the test for the result to be accurate.

For example, if you had a first-degree relative that passed away from colorectal cancer, you can have their tumor tested for biomarkers to see if perhaps they had a mutation. Most of the time hospitals store tumor specimens in tissue libraries and keep them even after a patient has passed away.

“I had no idea about biomarkers. I believe doctors should ask patients if they want to learn more about colorectal cancer. I did my own research and then asked questions. If I didn’t ask my oncology team about it I never would have known about mutations or biomarkers.”

–Mimi Pineiro, stage IV survivor

11. Does someone have pieces of my tumor so it can be tested?

Anything that is removed from a patient is sent to pathology by law. The pathologist will process the piece of the tumor and then keep the tumor. Pathology labs have libraries of tumor blocks, which are pieces of tumors fixed in chemical preservatives and embedded in wax to preserve them.

It is possible to use up the entire tumor. With each pathology process, a laboratory technician shaves thin slices of the tumor off to look at it under a microscope. Each time someone looks, they use up a bit of the tumor. If the tumor is small, the tissue can be exhausted. If it is larger, say the size of a walnut in its shell, there is abundant tissue to use for testing even years after the specimen is removed from the patient.

People absolutely can request biomarker testing on tumors that were removed in the past. However, for certain circumstances a fresh tumor biopsy can provide tissue for study that is more informative than what can be learned from an older specimen.

12. How would I go about finding that information and asking to test it?

Ask your doctor because they will have to order that testing. Have a conversation with your surgeon or your medical or radiation oncologist. 

Your surgeon or oncologist can request testing from the block that stores your tumor. When patients are referred to an academic institution the new center may request the tumor specimen to perform its own testing, and then return the block to the original institution where surgery was first performed.

13. Is it possible that the surgeon, oncologist, and radiologist already have biomarker information from a tumor, and all I need to do is ask for it?

It is possible that those tests were ordered but that the results were not shared with you. Generally, the medical team will discuss testing your tumor or blood before sending it off, unless it was done as part of a research study.

The reason for this is if a patient has a cancer susceptibility, a medical provider has the responsibility to tell the patient. Some people don’t want to know. Some people don’t want their insurance company to know because then their insurance may become aware of a pre-existing condition, for example.

Fortunately, now legislation says you cannot declare something a patient was born with to be a pre-existing condition. Instead, it’s considered a susceptibility.

“I had it done. It is so important to learn all you can about your diagnosis. Biomarker testing is a huge part of that process.”

–Chris Mullen, survivor

14. I’m afraid that the cancer in my body will “become worse” or “increase stage” while we are “waiting” to have biomarker testing done. Is this something that can be done after we start treatment? Or does it need to be done first?

Yes. Biomarker testing can be done after treatment is started. A person with colorectal cancer can begin the first cycle of chemotherapy since it may take two to three weeks for biomarker testing to come back. No one has to delay treatment because of biomarker testing although in some cases that may be recommended. In cases where testing may take some weeks to come back, treatment can be started and modified for later cycles of therapy. For example, immunotherapy can be added onto the treatment plan even after treatment is started, since immunotherapies of test results indicate that the patient has MSI colorectal cancer.

15. Should biomarker testing be done for only metastatic colorectal cancer?

Fight CRC would like to see biomarker testing done for any patient with a colorectal cancer diagnosis. There are compelling reasons to do biomarker testing for MSI early on when patients are first diagnosed. We are testing biomarkers for stage III patients. There was also a study at ASCO 2022, where MSI rectal cancer patients were treated with an immuno-oncology drug. All 14 patients had complete remission with the use of a single drug, which was much less toxic than chemo. While we don’t know the long-term outcome because these results are so new, we are hopeful that their complete remissions will be sustained. If this lead turns out to be true, as we all hope and expect that it will, it can potentially spare a subset of colorectal cancer patients – those with MSI – from having any chemotherapy, radiation, and surgery, and could eliminate those three modalities for MSI patients.

The colorectal cancer world is excited about this new development in treatment for patients, which will hopefully bring a less harmful treatment process to patients!

To Learn More

For more information on biomarkers and biomarker testing, please check out our Fight CRC resources. Our provider finder and clinical trial finder brings easy-to-use helpful, informative colorectal cancer-specific databases to your fingertips

Be Sure to Check Out These Fight CRC Resources

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