Colorectal cancer (CRC) is made up of many distinct subtypes that play a major role in your treatment options. Biomarker testing helps doctors understand the biology driving an individual tumor and choose therapies that are more likely to work.
As MD Anderson Cancer Center’s Dr. Scott Kopetz explains, “We use CRC to define anything that arises in that organ, but we know that there are different biologies and different behaviors.” Biomarkers help define those differences.
Below, Dr. Kopetz helps us break down the major biomarkers in CRC and what they mean for treatment.
MSI-H (Microsatellite instability–high)
MSI-H CRC is one of the most important biomarkers to test for because it has significant treatment implications.
“This is a subtype where there’s a problem repairing DNA,” Dr. Kopetz explains. When cells divide, their DNA isn’t fixed properly, so mutations build up quickly. As a result, “this tumor looks very different than any other tumor, night and day different than a normal lining of the colon.”
That difference is key. While most cancers look almost identical to normal cells, making them hard for the immune system to recognize, MSI-H tumors stand out. “The immune system already knows this cell may not belong,” Dr. Kopetz says.
Treatment implications
MSI-H tumors often respond well to immunotherapy. “All we have to do is nudge the immune system a little bit, and we can get really good and durable activity,” he explains.
Recent advances have changed the standard of care:
- For newly diagnosed metastatic MSI-H CRC, combination immunotherapy (PD-1 plus CTLA-4 inhibitors) has shown “really substantial improvements and outcomes that are clinically meaningful.”
- In earlier-stage disease, emerging data suggest that adding immunotherapy to chemotherapy in certain MSI-H stage III patients may improve outcomes.
BRAF mutations
BRAF-mutated CRC is another biologic outlier, and historically, one of the most challenging to treat.
“Before we had more effective treatments, this was a poor-prognosis subgroup,” Dr. Kopetz notes. These tumors behave differently, tend not to respond well to standard chemotherapy alone, and don’t respond to EGFR inhibitors by themselves.
Treatment implications
Progress has come from combination strategies:
- Targeted BRAF inhibitors combined with EGFR inhibitors became a standard approach.
- More recently, adding chemotherapy to BRAF + EGFR inhibition has shown major benefits.
“When you put that regimen together — BRAF, EGFR, and chemotherapy — you can actually double overall survival,” Dr. Kopetz says. “Those are really meaningful improvements.”
The idea is synergy: chemotherapy kills some cancer cells, targeted therapy kills others, and together they provide more complete disease control.
KRAS and NRAS mutations
KRAS and NRAS mutations are common and these mutations affect a key growth pathway that normal cells use for healing.
“This is a pathway that normally turns on to heal a wound and then turns off,” Dr. Kopetz explains. With KRAS, NRAS, or BRAF mutations, “that pathway is stuck in the ‘on’ position.”
Treatment implications
For most KRAS- or NRAS-mutated cancers, targeted treatments are still limited. However, there has been progress for a very specific subset:
- KRAS G12C mutations, found in a small percentage of patients, now have targeted inhibitors available.
- Combining a KRAS G12C inhibitor with an EGFR inhibitor has led to meaningful responses and FDA approvals.
- Ongoing studies are exploring how to move these treatments earlier in the treatment course.
While not every KRAS mutation is currently targetable, this progress represents an important step forward.
HER2 amplification
HER2 is another important biomarker, present in about 3-4% of CRCs. Unlike HER2-positive breast cancer, this usually isn’t caused by a mutation — it’s caused by extra copies of the HER2 gene.
“Instead of two copies, you might have 10, 15, or 20,” Dr. Kopetz explains. That leads to an overload of growth signals telling the cancer cell to keep dividing.
Treatment implications
There are now multiple ways to target HER2-amplified CRC:
- Dual HER2 blockade, often using an IV antibody plus an oral targeted therapy
- Antibody-drug conjugates (ADCs) — which Dr. Kopetz describes as a “Trojan horse” approach
“The antibody binds to the cancer cell, gets internalized, and then the payload is released to kill the cell from the inside,” he explains.
These therapies are showing promise and are increasingly being explored earlier in treatment.
When should biomarker testing be done?
Dr. Kopetz recommends biomarker testing as early as possible for patients with metastatic CRC.
“These are biomarkers we recommend testing in every patient whose disease has spread,” he says. “Test everyone, and test at diagnosis because it can really impact the first treatments patients receive.”
Guidelines are also evolving to include broader testing in earlier-stage disease, including emerging markers like PI3K mutations, which may help guide strategies such as aspirin use to reduce recurrence risk.
Circulating tumor DNA: A new way to detect cancer earlier
Circulating tumor DNA (ctDNA) is another powerful tool that’s changing CRC care. Instead of biopsying a tumor, ctDNA testing looks for cancer DNA fragments in the blood. This can be used in two key ways:
- Genotyping, to identify mutations like KRAS, BRAF, or PI3K
- Minimal residual disease (MRD) testing, to detect microscopic cancer left behind after surgery
Dr. Kopetz compares this leap to imaging advances: “Going from a chest X-ray to a CT scan gave us a hundred-fold improvement in sensitivity. ctDNA gives us another hundred-fold improvement beyond that.”
While ctDNA doesn’t show where cancer is, a positive result strongly suggests whether or not disease remains. This information is now being used to:
- Help decide whether adjuvant therapy is needed
- Monitor for recurrence earlier than scans
- Identify patients for clinical trials exploring new therapies
Biomarkers are transforming how CRC is treated, helping doctors move beyond one-size-fits-all care. As Dr. Kopetz emphasizes, understanding the biology of each tumor allows treatment to be more targeted, more effective, and increasingly personalized.
While there’s still more to learn, advances in immunotherapy, targeted treatments, and ctDNA testing are rapidly changing what’s possible for patients today.
View part two of our recap where Dr. Kopetz goes over the latest CRC research landscape.
