If you or someone you love has been diagnosed with metastatic colorectal cancer, one of the first questions may be: what treatment comes next?
There isn’t one treatment that works for everyone. Instead, doctors look at several factors, including where the cancer is located, how quickly it is growing, your symptoms and overall health, and, importantly, the genetic and molecular features of the tumor.
We asked USC Norris Comprehensive Cancer Center’s Dr. Heinz-Josef Lenz, a colorectal cancer expert, to explain how care teams decide which treatment path to pursue.
Chemotherapy is often the foundation of treatment
Several chemotherapy combinations are commonly used to treat metastatic colorectal cancer.
FOLFOX combines 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. Another option, FOLFIRI, combines 5-FU, leucovorin and irinotecan. In some situations, doctors may use all three chemotherapy drugs in a regimen called FOLFOXIRI.
FOLFOXIRI is a more intensive approach. As Dr. Lenz puts it, it’s essentially where “everything but the kitchen sink is used.” While this approach can be more effective for some people, it can also cause more side effects.
That means the decision isn’t simply about choosing the strongest treatment available. Your cancer care team will consider what the treatment is intended to accomplish and how well you are likely to tolerate it.
For example, Dr. Lenz explains that if someone has significant symptoms or a tumor that is causing a bowel obstruction, a more intensive treatment approach may be considered when appropriate.
Why genetic testing matters before treatment begins
One of the most important steps after a metastatic colorectal cancer diagnosis is biomarker or molecular testing.
These tests look for specific characteristics of the tumor that can help doctors determine which treatments are most likely to work. Among the important biomarkers are KRAS, NRAS, BRAF, HER2 and MSI/MMR status.
“The reason you need the genetic testing as soon as possible is because that determines the combination partner,” Dr. Lenz says.
MSI-high or dMMR tumors may respond especially well to immunotherapy
One particularly important result is whether the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
For people with metastatic MSI-H/dMMR colorectal cancer, immunotherapy can be an important first-line treatment option. Pembrolizumab, for example, is an established first-line treatment for metastatic MSI-H/dMMR colorectal cancer, and newer immunotherapy combinations are also changing the treatment landscape.
Dr. Lenz emphasizes why identifying these tumors matters: “These patients have a very high chance to be cured with immunotherapy alone.”
It’s important to understand that immunotherapy doesn’t guarantee a cure. Some people have long-lasting responses, while others may not respond or may eventually experience progression.
Other biomarkers can point toward targeted treatment
For tumors that are microsatellite stable, other biomarkers can help guide treatment.
For example, patients whose tumors are RAS wild-type may be candidates for treatments targeting the epidermal growth factor receptor (EGFR), particularly when the primary tumor is located on the left side of the colon or rectum.
Patients with certain mutations may instead benefit from drugs targeting other pathways.
For a BRAF V600E mutation, for example, targeted treatment involving encorafenib and cetuximab is now an important treatment option, including in the first-line setting when combined with chemotherapy in appropriate patients. The FDA granted traditional approval to encorafenib with cetuximab and fluorouracil-based chemotherapy in February 2026 based on results from the BREAKWATER trial.
What about HER2-positive colorectal cancer?
HER2 is another biomarker that can influence treatment decisions.
HER2-targeted treatments such as tucatinib and trastuzumab have shown activity in HER2-positive colorectal cancer. However, in the U.S., this combination is currently FDA-approved for certain patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer after prior chemotherapy, rather than as a standard first-line treatment.
Dr. Lenz points out that researchers are actively studying HER2-targeted approaches earlier in treatment. “There are a lot of developments, particularly in the HER2 pathway,” he says.
These studies are important because the goal is to determine whether targeted treatments can be moved earlier in the treatment sequence and help more patients benefit from them.
How will your doctor know if treatment is working?
Starting treatment is only the beginning. Your care team will regularly monitor your cancer to see how it is responding.
Before treatment starts, your doctor will typically obtain baseline imaging, often with a CT scan. Depending on where the cancer is located, additional imaging such as an MRI or, in certain situations, a PET scan may be useful.
Blood tests can also play a role. One commonly used tumor marker is carcinoembryonic antigen (CEA). Some doctors may also monitor CA 19-9.
Dr. Lenz explains that he uses these markers regularly to help track whether treatment appears to be working. However, tumor markers are only one piece of the puzzle. A change in CEA does not by itself prove that a treatment is or isn’t working, which is why doctors also use imaging, symptoms and other clinical information.
Dr. Lenz also monitors patients with CT scans relatively frequently, saying, “I want to know with the first CT scan that it works.”
The exact timing of scans varies from patient to patient and from one treatment plan to another.
Your treatment plan is personalized
For metastatic colorectal cancer, there is no single “best” first-line treatment for every patient.
Your oncologist may consider:
- Your tumor’s biomarkers and genetic alterations
- Whether the cancer is MSI-H/dMMR or microsatellite stable
- Whether the tumor has KRAS, NRAS or BRAF mutations
- Whether it is HER2-positive
- Where the primary tumor is located
- Whether the cancer is causing symptoms or complications
- Your overall health and ability to tolerate treatment
- Whether the goal is to shrink the cancer quickly, control the disease for as long as possible, or potentially make metastatic disease removable with surgery or another local treatment
- Whether a clinical trial may provide access to a promising new treatment
Perhaps most importantly, molecular testing can help ensure that your treatment is based not only on where the cancer started, but also on what is driving the cancer biologically.
For patients and families, that means staying informed about both currently available treatments and clinical trials can be an important part of making treatment decisions with your care team.
Learn more about second opinions and biomarkers for metastatic colorectal cancer, here.
