ctDNA: a new instrument for surveillance after ablative treatment

Finding tumour-specific DNA

Investigations of the clinical utility of circulating DNA in cancer treatment has gained strong interest during the past decade. The small free DNA fractions which are measurable in a simple blood sample are a mixture of DNA from both healthy and cancer cells. Therefore, it is possible to detect and measure DNA with tumour-specific characteristics in many different tumour types. The biology of ctDNA is far from fully understood, but development of laboratory methods for ctDNA measurement has been fast and impressive and now allows for large-scale clinical trials and explorative studies in many different tumour types.

ctDNA: our best chance to indicate recurrence risk early?

The presence of ctDNA in a blood sample indicates the presence of cancer cells in the body, since the half-life degradation of the cfDNA is only a few hours. Studies have shown that detection of ctDNA in blood samples from patients after a curatively intended treatment modality such as surgery implies an extremely high risk of recurrence of the disease. [1] This information is now being explored in multiple clinical trials in primary colorectal cancer investigating the use of ctDNA as a marker of minimal residual disease (MRD), as a tool for guiding adjuvant systemic therapy and follow-up programmes. [2] The potential for this is very promising, and the first results from clinical trials were presented last year. [3] In the follow-up programme after cancer treatment, the sensitivity of ctDNA detection may exceed the clinical and imaging-based assessments, and studies have described a clinical lead time between the ctDNA based detection and the clinical determination of recurrences from months to years. Clearly, this calls for prospective testing in multiple tumour types to investigate if ctDNA testing can provide clinically relevant early detection of treatment failure and recurrences. This is particularly relevant in the high-risk situations such as after local ablation of metastatic lesions.

Now, where should this method best be used?

The detection rate of ctDNA in low-risk disease can be limited, whereas patients with spread of the disease to other organs, especially the liver, show higher concentrations in their blood. [4] In the clinical situation with oligometastatic disease which could allow for local ablative therapies, there is an unmet need for reliable tools to select patients for active strategies, and to support decisions of post-treatment adjuvant therapy and follow-up schedules. The potential of ctDNA as pre-and post-treatment prognostic factor is presented in a recent review in colorectal cancer. [5] As adjunct to advanced imaging procedures, the ctDNA guided strategies can become highly valuable. Therefore, prospective observational studies that investigate the biological clearance of ctDNA after the different ablative options are urgently needed, since still only a limited number of studies have been published on ctDNA detection in the oligometastatic setting. The full potential is clearly far from described. The shedding and mutational recovery from the different organs needs to be elucidated, as does the potential role of combining ctDNA with advanced imaging and AI tools.

Very few prospective studies have been initiated to investigate ctDNA guided treatment and follow-up in a randomized stringent way, and more such initiatives should be undertaken to confirm the great potential ctDNA testing can have in this clinical setting.

I look forward to presenting an overview of the current knowledge on ctDNA biology, methodology, and the huge clinical potential for its use. In addition, I will discuss some of the few clinical trials designed to prospectively investigate its clinical utility in oligometastatic disease.