Liquid biopsies for adjuvant therapy: a better tool for a difficult decision

Cancer cells shed fragments of DNA into the blood, where it is known as circulating tumour DNA (ctDNA). Patients who have ctDNA remaining in the blood after cancer surgery are known to have a higher risk of their cancer returning, but it has been unclear if this knowledge can be used to improve treatments for patients.

Recent results from the DYNAMIC trial now provide firm evidence that for colorectal cancer, blood tests or ‘liquid biopsies’ can help identify those patients who will benefit from additional chemotherapy following surgery, and those who can be spared further treatment.

To treat or not to treat

Following surgery to remove cancer, a decision often must be made as to whether the patient should receive additional (adjuvant) chemotherapy. This is to remove any remaining traces of cancer and reduce the risk of the cancer returning. However, for patients with colorectal cancer, this can be a difficult decision to make.

Whilst patients with more advanced Stage III colorectal cancer are always offered adjuvant chemotherapy, for those with less advanced Stage II cancers it is only recommended if they are considered at high-risk of relapse. The difficulty is that it is often unclear whether a patient is at high or low risk. Many patients identified as ‘ high risk’ based on conventional clinical features (such as how abnormal their tumour cells appear) never go on to relapse, whilst others classed as ‘low risk’ do. This means some patients go through unnecessary treatment as a precaution, which takes a toll on their time and health, whilst others who could have benefited may miss out.

ctDNA liquid biopsies as a new tool to predict recurrence

Liquid biopsies to detect ctDNA may be useful for a variety of purposes, including selecting treatments, as we have previously described. One of the more novel and promising uses of ctDNA is as a tool for adjuvant therapy selection. For Stage II colorectal cancer, patients with detectable levels of ctDNA after surgery are approximately 18 times more likely to relapse than those with no ctDNA detected. This has raised hopes that the presence or absence of ctDNA could be used to help identify which Stage II colorectal cancer patients should be offered adjuvant chemotherapy. The DYNAMIC trial was one of the first large randomised and controlled trials launched to address this question, and now provides some of the answers.

ctDNA is a better tool for adjuvant therapy selection

The DYNAMIC trial randomly allocated 455 Stage II colorectal cancer patients into two groups. One group received standard management based on conventional clinical assessment. Of these, 28% were offered adjuvant chemotherapy. The second group had their blood tested for ctDNA at four and seven weeks post-surgery. Only when ctDNA was detected were patients offered adjuvant chemotherapy-15% of the group.

The overall likelihood of remaining cancer-free within a two year time period was the same in both groups (over 92%) despite less patients in the ctDNA-guided group receiving adjuvant therapy.  This supports the hypothesis that using ctDNA more effectively differentiates between patients who will benefit from chemotherapy and those who won’t; in this study almost half of the patients in the ctDNA group who would otherwise have been given unnecessary treatment were safely spared.

Stronger together?

No single biomarker can perfectly predict disease recurrence, and ctDNA is no exception. In this study ctDNA was used alone, however in future, using ctDNA alongside other clinical risk could help clinicians and patients make therapy decisions with yet more confidence.

In the DYNAMIC trial, 96.7% of ctDNA negative patients whose clinical features indicated a low risk of the cancer retuning were predicted to be cancer-free after three years. The study authors argue this firmly suggests that these patients should not receive adjuvant therapy.

On the other hand, in ctDNA negative patients with high risk clinical features, the likelihood of remaining cancer free at three years was lower at 85.1%. For these patients, decisions over withholding adjuvant therapy will need careful consideration, potentially taking other risk factors into account. Further evidence from other studies is needed on these integrated risk assessment approaches, including stratifying the risk of ctDNA positive patients in order to inform treatment decisions.

Preparing for implementation

We now have much firmer evidence that ctDNA can be useful for adjuvant therapy decisions in colorectal cancer, but several outstanding questions remain which can be addressed by ongoing and future trials. The answers should clarify not just use of ctDNA in colorectal cancer, but hopefully be informative for other cancer types too;

• Could patients benefit from more rapid ctDNA testing enabling earlier treatment? In this study ctDNA patients faced an average treatment delay of 30 days, due to the turnaround times of the test.
• Could performing several sequential tests improve the accuracy of results and the effectiveness of treatment?
• What is the long term prognosis for these patients? There is a chance that treating ctDNA positive patients didn’t actually prevent recurrence, only delayed it – continuing to collect data from patients over longer time periods after they have been treated will help to answer this question.
• Can ctDNA be used with other biomarkers to further stratify patients into even more refined risk categories, allowing even better treatment selection?
• Does the type of adjuvant therapy used affect the ability to use ctDNA to guide decision making?

Meanwhile, there are other practical issues to consider if ctDNA testing is to become more widely used, for example how laboratories should choose which type of ctDNA test technology to use. With the evidence for utility growing, perhaps the time is now right to start thinking about how this type of ctDNA testing can be implemented into mainstream clinical practice?