Circulating tumour DNA analysis can help identify the need for adjuvant therapy in stage II colon cancer

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Published: 4 Jun 2022
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Dr Jeanne Tie - The Peter MacCallum Cancer Centre, Melbourne, Australia

Dr Jeanne Tie talks to ecancer about her study on circulating tumour DNA analysis and how it can help identify the need for adjuvant therapy in stage II colon cancer.

The role of adjuvant chemotherapy (CT) in stage II colon cancer continues to be debated. The presence of circulating tumour DNA (ctDNA) after surgery predicts very poor recurrence-free survival (RFS), while its absence predicts a low recurrence risk.

Patients were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria), after stratification for T stage.

Dr Tie notes that the primary efficacy endpoint was non-inferiority in RFS rate at 2 years. A key secondary endpoint was adjuvant CT use. The target sample size of 450 provided 80% power with 95% confidence to confirm non-inferiority between the two arms with a margin of 8.5%.

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The study I was presenting is called a dynamic study where the main aim is to demonstrate that using a blood test called circulating tumour DNA can actually reduce the use of chemotherapy in patients with stage 2 colon cancer. As a way of background, currently the way we manage stage 2 colon cancer is a huge clinical dilemma in the clinic because surgery can cure more than 80% of patients and the use of adjuvant chemotherapy only improves outcomes for these patients less than 5%. So we’re clearly over-treating a lot of these patients and there isn’t a way where we can select which patients will recur and which will not recur accurately. So we’re hoping that using ctDNA to be able to predict who is going to recur quickly and who is not going to recur, or have a lesser risk of recurrence, to help us better stratify which patients will need chemotherapy or not. 

So that is essentially the background. Previous work that we’ve done has certainly shown that if you have a positive ctDNA or detectable ctDNA after surgery for stage 2 colon cancer and you’re not treated with adjuvant chemotherapy your risk of recurrence is extremely high, it’s over 80%. So we’re hoping that with our study, which we’ll talk about soon, is that using the results of the ctDNA that we can guide who will need treatment and who doesn’t need treatment.

The study essentially is a randomised study where we allocate a group of patients to ctDNA guided management where if they have a positive test they receive chemotherapy, if they don’t have a positive test or have a negative test they’re not treated with chemotherapy, they just undergo observation or surveillance. The control group is essentially our standard management group where clinicians manage the patients without the blood tests. So they manage the patient based on the conventional clinical pathological risk features such as T stage and number of lymph nodes, lymphovascular invasion – typical risk factors that clinicians will look at to decide whether the patient will need chemotherapy or not. So that’s the comparator arm and we’re essentially comparing the outcome of the two looking at the use of chemotherapy between the two groups of patients as well as the recurrence free survival. We want to demonstrate that we can reduce the use of chemotherapy but not compromising on the risk of recurrence or recurrence free survival.

We recruited 455 patients in 23 Australian centres over a four-year period from 2015 to 2019 for the study. What we found was that the use of ctDNA guidance reduced the percentage of patients requiring chemotherapy from 28% in the standard care arm down to 15%, so almost half the number of patients requiring chemotherapy. Importantly, we also demonstrated that the recurrence free survival between the two arms was similar. So no detrimental effect in terms of outcome but we reduced the number of patients receiving chemotherapy for the main finding.

How similar were the trial arms?

The three year recurrence free survival was 93.5% in the ctDNA guided arm and 92.4% in the standard management arm. If there is access to ctDNA testing in the clinic I would definitely, tomorrow if I go back to the clinic, be using ctDNA to help me guide which patients will need chemotherapy or not. The study result is pretty conclusive that we are not affecting patients’ outcome and can reduce patients’ chemotherapy use. It’s just really another tool that we can use in the clinic in addition to our standard pathological risk features to help us decide whether patients will benefit from chemotherapy.

ctDNA assay for what we call minimal residual disease testing is available in the US commercially. There are several different assays that market it for the use. The assay that we use for our study is actually a research-based assay, it’s not yet commercially available. So the big question is can the result of the study be extrapolated to other assays. Hard to say at this stage, I think each of the assays do perform very differently; even though they all say that they have certain sensitivity they’ve never been compared head to head. So I would be cautious or uncomfortable in recommending using other assays for use based on our result at this stage. 

There was one other important finding that was a secondary objective was that we found that even in the ctDNA positive patients who received chemotherapy, historically they do really badly, they have a recurrence free survival usually about 20% or less. In our study they’re above 80%, their recurrence free survival. So that really suggests that adjuvant chemotherapy will actually benefit this very well-defined subgroup of patients.