Analysing tumour DNA in blood samples from people who have undergone surgery for colorectal cancer can detect whether the cancer has disappeared or is returning. It also enables doctors to determine how rapidly the cancer is developing and thus stratify patients according to risk, says a researcher.
The preferred treatment for people with colorectal cancer without metastasis is surgical removal. This is supposed to cure the cancer, but up to 30% experience recurrence. This typically happens because the cancer had already spread as micrometastases at the time of surgery.
Everyone with stage III colorectal cancer currently undergoes chemotherapy after surgery to eliminate micrometastases and avoid recurrence.
However, chemotherapy is not foolproof, has major side-effects and is only required for the 30% with recurrence.
Doctors could not previously determine who has been cured by surgery and therefore do not need chemotherapy and who is likely to benefit from more treatment.
This may change, however, since researchers have found that circulating tumour DNA in the blood – DNA fragments from cancer cells – can reveal whether cancer remains or whether surgery eliminated it.
Analysing tumour DNA can thus presumably categorise such people according to whether they should receive chemotherapy or have been completely cured.
“Chemotherapy can have very serious side-effects, some of which are lifelong. We would very much like to avoid treating healthy people with chemotherapy but cannot completely avoid this today. However, blood samples from people who have had surgery for colorectal cancer enables us to determine whether they still have cancer, requiring chemotherapy,” explains Claus Lindbjerg Andersen, a researcher behind the study and Professor at the Department of Clinical Medicine at Aarhus University, Denmark.
The research has been published in the Annals of Oncology.
Tumours constantly release DNA into the blood
People with cancer have constant turnover of cancer cells – some die and others are added. When a cancer cell dies, some of its contents, such as its DNA, can be released into the environment and enter the bloodstream.
The DNA of cancer cells is mutated, differing at specific points from normal DNA. Researchers use these differences between the tumour DNA and the normal DNA as markers when they look for tumour DNA in a blood sample.
Further, free DNA in the blood does not survive very long. After a few days it is gone, and if the tumour is completely removed, no new tumour DNA will enter the blood.
“We can therefore analyse tumour DNA to determine whether the tumours have been completely removed or there are still tumour cells left,” says Claus Lindbjerg Andersen.
He elaborates that people differ in the risk of recurrence after surgery for colorectal cancer.
People with stage 1 cancer have about 5% risk of recurrence; stage 2, 10–15%; and stage 3, 25–30%.
“The increased risk of recurrence in stage 3 requires initiating chemotherapy in contrast to the other two stages. Because of the risk of recurrence, everyone undergoing surgery is currently offered follow-up with scanning for three years after surgery; 70% are cured and the cancer will not recur, so this approach is inappropriate, since much of the health resources used for follow-up today have no benefit. The challenge is again that we do not know in advance who will relapse and thus need follow-up,” explains Claus Lindbjerg Andersen.
851 people with colorectal cancer in the study
The researchers validated the use of tumour DNA to identify residual disease among 851 people who underwent surgery for colorectal cancer by analysing several repeated blood samples.
The researchers analysed both blood samples taken immediately after surgery and those taken up to three years after surgery.
The researchers also compared the risk of recurrence as measured by tumour DNA with the traditional method of determining the stage of the tumour at surgery.
All participants had stage 2 or 3 disease, and many had had chemotherapy after surgery.
Better marker than classic staging
The results show that the presence of tumour DNA in the blood immediately after surgery is better at predicting who will experience recurrence than the staging of the tumour in connection with the surgery.
Specifically, the researchers found that the presence of tumour DNA in the blood immediately after surgery was associated with a 10-fold increased risk of recurrence compared with not having tumour DNA in the blood.
“This makes tumour DNA a much better marker for recurrence than the classical targets,” says Claus Lindbjerg Andersen.
He estimates that a free choice between these two markers would probably favour tumour DNA as the method for assigning chemotherapy and scanning.
“Before we can change practice, the two methods must be compared in a randomised trial. Such a study must show that measuring tumour DNA can also lead to less chemotherapy without this also resulting in more recurrence,” adds Claus Lindbjerg Andersen.
Monitoring tumour growth after recurrence
According to Claus Lindbjerg Andersen, analysis of tumour DNA has another advantage: monitoring the development of cancer not completely removed by surgery.
A person with colorectal cancer would have detectable tumour DNA in the blood about one month after surgery. Another blood sample the next month could determine the amount of tumour DNA in the blood and thereby how much the tumour has grown.
If the size of the tumour doubles in a month, the situation is critical and doctors must respond strongly. But if the tumour has barely grown in one month, waiting may be better.
“I think that this very possibility of monitoring the tumour burden after surgery is going to be very important in the future approach for people with colorectal cancer. If the tumour grows quickly, the risk of dying increases significantly, and this signals a narrow window for treatment. If the tumour grows slowly, the treatment window is longer. This can also affect the priority we give to each individual,” explains Claus Lindbjerg Andersen.
He estimates that this opportunity to stratify according to risk can also be very important for clinical studies with new treatments.
The characteristics that cause some tumours to grow more rapidly or slowly when they recur can influence the effectiveness of new treatment.
“We might find that some treatments work really well for the tumours that grow rapidly when they recur, and others work well for tumours that grow slowly. Analysis of tumour DNA can help to establish this kind of insight,” concludes Claus Lindbjerg Andersen.
