ctDNA Biomarker

Circulating tumor DNA (ctDNA) is small fragments of DNA from tumor cells that can be detected in the blood. When tumor cells die, they release ctDNA into the bloodstream.

CtDNA is both a predictive and prognostic biomarker. Predictive markers can help to determine the likelihood that a person’s tumor is likely to respond to or be resistant to a particular treatment program. Prognostic markers provide information on whether an individual’s cancer is likely to behave in an aggressive or less aggressive manner. Testing for ctDNA is used for a variety of reasons and may occur at various timepoints throughout treatment. Some reasons your medical team may recommend ctDNA testing include:

• To test for minimal residual disease (MRD) after surgery – testing is often performed 4+ weeks after curative surgery to assess MRD status. MRD is a term that applies to evidence that a person has tumor deposits or tumor cells in their body that are not detectable on x-rays or scans.  This is most common in patients diagnosed with stage II or III CRC. 
• To monitor for recurrence after successful treatment –testing is generally performed 2+ weeks after the completion of systemic treatment. This is most common in patients diagnosed with stage IV or metastatic CRC.
• To predict treatment response – testing for ctDNA is typically conducted every 8-12 weeks for monitoring treatment response. Lower levels of ctDNA suggest that the treatment is working, while rising counts suggest treatment resistance.
• To determine the status of other biomarkers, or ctDNA molecular profiling – testing can be used to assess other biomarkers in place of tumor tissue-based sequencing. This means the profiling can be done through a blood test rather than a biopsy.

CtDNA is a type of circulating-free DNA (cfDNA). CfDNA can be derived from any cell type, including “normal” healthy cells. CtDNA is specifically DNA found in the bloodstream that is derived from tumor cells.

CtDNA is tested using a blood sample, or liquid biopsy. Next-generation sequencing (NGS) may be used to analyze ctDNA to determine the status of other biomarkers.

A “positive” ctDNA test can mean many things depending on the primary reason for testing.

Following surgery for stage II or III CRCs, testing is usually preformed to look for the presence of ctDNA. If ctDNA is present, your report may say “ctDNA detected” or “ctDNA positive.” The presence of ctDNA after tumor resection is highly predictive of early disease recurrence or minimal residual disease. Conversely, no ctDNA detected in a liquid biopsy may be reported as “ctDNA negative” or “ctDNA undetectable.”

• If your test is positive after surgery, your risk for recurrence will be considered high. Your medical team may recommend starting or adjusting adjuvant chemotherapy.
• If your test is negative after surgery, your risk for recurrence will be considered low. Your medical team may recommend a change in the type or duration of  adjuvant chemotherapy.

Patients who complete treatment (surgery alone or in combination with chemotherapy and/or radiation) may undergo testing to look for the presence of ctDNA. This would be to monitor for recurrence after completing therapy. If ctDNA is present, your report may say “ctDNA detected” or “ctDNA positive.” The presence of ctDNA after tumor resection is highly predictive of early disease recurrence or minimal residual disease. Conversely, no ctDNA detected in a liquid biopsy may be reported as “ctDNA negative” or “ctDNA undetectable.”

• If your test is positive after completing treatment, your medical team will likely order a follow test after the passage of time and/or imaging tests to look for recurrent cancer.
• If your test is negative after completing treatment, you do not have detectable recurrence. However, this does not mean that there is  no chance of a recurrence being detected in the future as some tests may be negative if the amounts of ctDNA are too low to be detected at the time the test is done. Your medical team should continue to monitor you.  

Patients diagnosed with stage IV or metastatic CRC will likely have testing before and during treatment, called serial ctDNA measurement. In these cases, ctDNA levels will often be reported as a number or level. These numbers can be used to predict your response to treatment. A decreasing ctDNA level during treatment predicts a good response to treatment. An increasing ctDNA level during treatment predicts a poor response to treatment and indicates disease progression.