Levels of cell-free DNA do not impact ctDNA detection in patients with CRC

January 2023

There is increasing evidence to support the use of circulating tumour DNA (ctDNA) as a biomarker to detect minimal residual disease (MRD) in colorectal cancer (CRC).

Biomarker: a molecule that can be found in the the body (e.g. in the blood or tissues) that can be used as a sign of a normal or abnormal process, or as a indicator of a specific disease.

What is ctDNA?

ctDNA refers to the DNA or genetic material that comes from cancer cells and tumours. Normally DNA is stored inside a cell, but as a tumour grows, its cells die and are replaced by new ones. The dead cells release their contents, including their DNA, into the bloodstream. ctDNA are the pieces of DNA that can be detected in the blood.

Measuring quantities of ctDNA can be helpful to:

• Detect and diagnose a tumour. ctDNA is different from a patient’s DNA, since tumours acquire genetic changes that result in changes to their DNA. In this way, analyzing ctDNA can help to identify specific mutations that are present in the tumour, and serve as a potential guide to determining which treatments the tumour is most likely to respond to

• Monitor how a tumour is responding to treatment. A decrease in the overall quantity of ctDNA suggest that tumour is responding to treatment and shrinking in size. In the context of colorectal cancer, ctDNA testing can help to determine whether someone who has undergone surgery would benefit from additional chemotherapy.

• Monitor periods when the cancer is in remission. A consistent lack of ctDNA in the blood after treatment suggests that the cancer has not come back (recurred)

ctDNA is different from cell-free DNA (cfDNA), which is a broader term that refers to DNA that is circulating in the bloodtream but does not necessarily come from a tumour and can come from normal tissues. cfDNA levels can increase after a patient receives survery, and when patients receive chemotherapy.

The study

A concern with the timing of MRD ctDNA testing has been that immediately after a patient undergoes surgery when there will be an increase in cfDNA, that those elevated levels could make it harder for precise ctDNA levels to be measured. As such, ctDNA testing to evaluate the tumour response to surgery was not being done until 4 weeks post-surgery. Timing is of the essence with MRD testing, as waiting too long to test can result in delays in treatment.

At the 2023 ASCO GI Symposium, findings from a large US-based study found that standard MRD testing could be done as early as 15 days (2 weeks) after surgery, since levels of cell-free DNA were found to not negatively impact ctDNA detection. There was no association found between cfDNA concentration and whether ctDNA could be detected.

Conclusion 

While there are changes in the quantities of cfDNA after surgery, the changes appear to be most noticeable in the first week and second week after surgery. By 15 days, cfDNA levels appear to remain consistent and ctDNA levels are able to be detected.

Although MRD testing is not yet a standard of care for patients with colorectal cancer who have undergone surgery, the study findings suggest that this testing can be done sooner after surgery than previously thought. This provides an important benefit to patients as it could enable patients to receive further chemotherapy in a more timely fashion, if it is deemed necessary.