What recent ctDNA research means for colorectal cancer patients

For people diagnosed with colorectal cancer (CRC), one of the hardest parts of treatment is uncertainty: Did surgery remove all of the cancer? Is treatment working? Could the cancer come back before it appears on a scan?

Circulating tumor DNA (ctDNA) is helping doctors answer some of these questions with a simple blood test. This tool is still evolving, and while it’s not appropriate for every patient or situation, research over the last few years has shown that it may help personalize treatment decisions and detect recurrence earlier than traditional imaging alone.

What is ctDNA?

Circulating tumor DNA refers to tiny fragments of DNA shed by cancer cells into the bloodstream. After surgery or during treatment, doctors can analyze a blood sample for these fragments to look for signs of remaining cancer cells, also called minimal residual disease (MRD).

Unlike a traditional biopsy, ctDNA testing is minimally invasive and can often be repeated over time to monitor changes in the cancer.

Researchers are studying ctDNA across many cancer types, but CRC has become one of the leading areas where this technology is being used clinically and in research.

How ctDNA is currently being used in CRC

1. Estimating recurrence risk after surgery

One of the biggest current uses of ctDNA is after surgery for stage II and stage III CRC.

Even when scans show no visible cancer, microscopic cancer cells may still remain in the body. Studies consistently show that patients with detectable ctDNA after surgery have a much higher risk of recurrence compared with patients whose ctDNA is negative.

This information may help doctors decide:

• Whether chemotherapy is needed after surgery
• How intensive treatment should be
• Which patients may benefit from closer monitoring

For some patients, ctDNA-negative results may help avoid unnecessary chemotherapy and its side effects. For others, a positive ctDNA result may signal the need for additional treatment or clinical trial enrollment.

The large BESPOKE CRC study showed that ctDNA testing helped guide treatment decisions in stage II and III CRC and provided important information about recurrence risk.

Why this matters for patients

Traditionally, doctors have relied on tumor stage and pathology features to estimate recurrence risk, but these tools do not always predict who will relapse.

ctDNA offers a more personalized approach because it reflects what may actually still be happening in the body after treatment.

For patients, this could mean:

• More confidence in treatment decisions
• Fewer people receiving unnecessary chemotherapy
• Earlier intervention if cancer returns
• More individualized surveillance plans

2. Monitoring for recurrence earlier

ctDNA may also detect recurrence months before cancer becomes visible on imaging scans.

A recent review of studies found that postoperative ctDNA positivity often predicted recurrence before radiographic relapse was identified on scans.

Researchers are also studying how ctDNA changes over time. Investigators reported that tracking ctDNA dynamics longitudinally may help more precisely estimate relapse risk in colon cancer.

This earlier warning could eventually allow doctors to:

• Start treatment sooner
• Monitor treatment response more closely
• Identify recurrence before symptoms develop

However, experts caution that ctDNA should currently be used alongside scans, physical exams, and other monitoring tools, not as a replacement for them.

3. Helping guide treatment in metastatic CRC

ctDNA is also becoming increasingly useful in metastatic colorectal cancer (mCRC).

In advanced disease, ctDNA testing can help identify genetic mutations that may affect treatment selection, including mutations in genes such as RAS and BRAF.

Researchers are also studying whether ctDNA can help determine when certain targeted therapies may work again after resistance develops.

Findings from the REMARRY and PURSUIT trials presented at the 2025 ASCO Annual Meeting showed that longitudinal ctDNA monitoring may help predict which patients with mCRC could benefit from anti-EGFR rechallenge therapies.

This type of “real-time” molecular monitoring may help doctors adapt treatment strategies more quickly than relying on scans alone.

Important limitations patients should know

While ctDNA is promising, it is not perfect.

There are still important limitations:

• Some cancers shed very little DNA into the bloodstream
• False negatives can occur
• Not all positive results lead to visible recurrence
• Different ctDNA tests may perform differently
• Researchers are still determining the best timing and frequency for testing

Most experts currently view ctDNA as an additional tool, not a standalone answer.

Is ctDNA testing standard of care?

ctDNA testing is increasingly being incorporated into clinical practice, especially for CRC, but its use varies depending on the patient’s cancer stage, treatment history, and access to testing.

Many cancer centers now offer ctDNA testing in certain situations, particularly:

• After surgery for stage II or III CRC
• During surveillance after treatment
• In metastatic disease for molecular profiling and monitoring

Ongoing clinical trials are working to determine exactly how ctDNA-guided care should shape future treatment guidelines.

The future of personalized CRC care

Researchers believe ctDNA could become a central part of precision oncology in CRC.

Future goals include:

• Better identifying who truly needs chemotherapy
• Detecting recurrence earlier
• Monitoring treatment effectiveness in real time
• Matching patients to targeted therapies or clinical trials faster
• Potentially improving survival while reducing overtreatment

Although more research is still needed, ctDNA is already helping move CRC care toward a more personalized and less one-size-fits-all approach.