You Are Unique.
So is your tumor.
Knowing your colorectal cancer biomarkers can help your doctors identify your best treatment options. This can 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.
Biomarker is short for biological marker. Biomarker testing is sometimes called tumor testing, molecular testing, and genomic testing. 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 give 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 in a person after treatment.
Most biomarkers are proteins which are coded for by tumor cell DNA. Their presence shows that there are genomic abnormalities (or changes) that distinguish tumor cells from healthy cells. Also, their presence can provide clues to what drives the cancer cells to grow and spread. These abnormal proteins can be found in cancer cells or in the cell membranes of those cells. They can be detected by tests done directly on tumor tissue or on body fluids, most commonly blood. By understanding an individual tumor’s biomarkers, doctors can predict how the tumor may grow and spread in addition to whether or not it may respond to specific treatments.
Your colon or rectal tumor might not respond to the same treatment that other colorectal cancer patients receive depending on the changes (biomarkers) within your tumor. Addressing your course of treatment by learning the specific genomic changes of your cancer—your colorectal cancer biomarkers—will help your team deliver care that will be the most beneficial with the least amount of side effects. Learn more about specific colorectal cancer biomarkers below.
Colorectal Cancer Biomarkers
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.
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 means a tumor does not have a KRAS mutation. Patients who’s 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 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 is a gene that signals cells to divide. Approximately 1% of patients with metastatic CRC 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 metastatic CRC. 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-high as a way to help determine if the MSI-H status if the tumor is inherited or acquired. There are specific drugs and drug combinations which target BRAF mutations.
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 metastatic CRC. Approximately 20% of patients with BRAF V600E–mutated metastatic CRC also have microsatellite instability. Just like any other patients with microsatellite instability, 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 microsatellite-stable CRC.
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 CRC0 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-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 cancer 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 metastatic CRC 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 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 metastatic CRC (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.
CEA tests are part of follow-up care and monitoring for stage II, III, or IV patients with all known diseases resected and once active treatment is completed. CEA tests are recommended every 3-6 months during the first and second year after treatment ends, and every 6 months during the third, fourth, and fifth year after treatment ends.
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 (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. This suggests that anti-HER2 therapy may be effective in this group of metastatic CRC (mCRC) patients. There is also evolving evidence that HER2 amplification may cause resistance to EGFR inhibitors. Currently there are no recommendations for routine testing for HER2 in CRC.
Currently, there are no recommendations for routine testing for HER2 in CRC.
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 metastatic CRC have recently been approved, including entrectinib and larotrectinib. These have been approved for metastatic solid tumors who have either progressed following prior therapies or as initial therapy when there are no acceptable standard therapies.
Things to Consider when Choosing Treatment
It’s vitally important to talk to your doctors about your colorectal cancer biomarkers (aka tumor type), as soon as possible after your diagnosis and before treatment begins. This information can help you make the best treatment decisions. It’s also important to consider the following factors before beginning treatment.
Biomarker (Tumor) Testing VS Genetic Testing
There can be a lot of confusion when it comes to the types of testing received. Learn the difference between some of the most common terms.
Right VS. Left
Ask your doctor about the “sidedness” of your tumor. Whether it was on the right or left side of the colon can make a difference.
LEARN ABOUT YOUR BIOMARKERS
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 A.I. 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.
You Are Not Alone
Deborah & Ronnie
They vowed in sickness and in health – which included colorectal cancer.
Learn the different types of cancer testing, specifically tumor testing versus genetic testing and all the terminology that goes along with it.
As a complex GI oncology nurse, she explains the role of biomarker testing and the importance of patients and doctors working together.
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!
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?
Biomarker (tumor) testing is becoming more common, especially in clinical trials. It is a new step in the treatment process that is still on a journey of reaching all oncologists and providers.
Can I be BRAF and KRAS positive?
It would be extremely rare. If you have a BRAF-mutant tumor you will not be KRAS mutant, and vice versa.
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.
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The evidence-based guideline for molecular testing for colorectal cancer is a joint publication between the four organizations: American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.
The complete title of the guideline is: 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
Martin V, Landi L, Molinari F, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer. 2013;108:668–675.
National Comprehensive Cancer Network. https://www.nccn.org/
Siena S, Sartore-Bianchi A, Lonardi S, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. J Clin Oncol. 2015;33 abstract 3508.
Biomarked is dedicated to the memory of Clint Cummings, owner of Sparrows Tattoo Company and stage IV colorectal cancer fighter. Clint was passionate about raising awareness with his story. Biomarked uses tattoos to create awareness about a lifesaving topic for colorectal cancer patients and works to break the still-present taboo surrounding colorectal cancer to get people’s attention.