Using the ‘very promising technology’ to guide treatment decision-making led to similar recurrence-free survival compared to standard practice.
Long-term survival data in early colon cancer patients suggests ctDNA guided chemotherapy use is noninferior to management based on conventional clinicopathological criteria in certain subsets.
“There’s good or emerging evidence that ctDNA can help our understanding of prognosis in many solid tumours,” said Associate Professor Katrin Sjoquist, a medical oncologist from St George Private Hospital who was not involved in the new research.
“It can potentially predict benefit from treatment, as this study it can identify participants for clinical trials in certain cases. It has an emerging use in tracking the development of resistance to cancer treatments.”
The use of ctDNA as a “liquid biopsy” in patients with colon cancer has previously been explored through the Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage II Colon Cancer (DYNAMIC) trial.
As part of this trial, the management of 455 patients with stage II colon cancer was randomised to be guided by their ctDNA status or by standard management in a 2:1 fashion.
Patients in the ctDNA group with a positive ctDNA analysis received chemotherapy, while patients with a negative ctDNA analysis were observed. Patients in the standard management group received treatment bases on conventional clinicopathological criteria.
Early data from the DYNAMIC trial, published in the New England Journal of Medicine, suggested that ctDNA-guided management was non-inferior to standard management, with two-year recurrence-free survival rates (94% versus 92%) similar between the two groups and a smaller proportion of ctDNA-managed patients receiving adjuvant chemotherapy (15% versus 28%).
Now, new follow-up data, published in Nature Medicine, compares how ctDNA-guided management and standard management perform five years later. While five-year overall survival rates were similar between the two groups (94% versus 93%), overall survival rates were poorer when comparing ctDNA-positive and ctDNA-negative patients in the ctDNA-guided management group (86% versus 95%).
Recurrence-free (88% versus 87%) and colon-cancer specific survival (98% versus 97%) rates were also similar between the ctDNA-guided and standard management groups, as was overall and recurrence-free survival when patients with T4 stage.
When ctDNA levels and clearance rates were considered, 35 of the 40 patients (87%) who underwent ctDNA analysis pre- and post-chemotherapy displayed ctDNA clearance (ctDNA positive pre-treatment to ctDNA negative post-treatment).
“Clearance was achieved in 24 of 26 (92.3%) patients treated with oxaliplatin doublet chemotherapy and 11 of 14 (78.6%) patients treated with single-agent fluoropyrimidine chemotherapy,” the researchers noted.
Having a higher ctDNA molecular burden at baseline was associated with a lower post-treatment ctDNA clearance rate, and patients with a higher ctDNA burden were over 10 times more likely to experience disease recurrence within five years.
Professor Sjoquist said the lower recurrence free survival rate in patients with an increased ctDNA burden was “not surprising”.
“We know from previous work done by this team and others that having positive ctDNA that persists after surgery has a worse prognosis. That means they are the group that will potentially benefit the most from chemotherapy, but they were also most likely going to have a worse outcome,” she told The Gut Republic.
The researchers concluded that ctDNA burden could be considered as a way of stratifying patients in future studies of ctDNA-informed therapy.
Professor Sjoquist agreed there was potential for future research to explore how ctDNA analyses could be used to guide more effective decision-making regarding chemotherapy use in these patients, but acknowledged there were significant barriers before such approaches could be used extensively throughout clinical practice.
“The specific test that was done as part of this trial is not available commercially. There are commercial tests that are becoming available that are based on slightly different methodologies, but as yet, there is no funding within the MBS for this testing – and the one that I am most familiar with is $1700 USD for a single test at one time point,” she said.
“The barriers to implementation at the moment for many people are costs and access, although this may improve in the future as the technology evolves.
“[ctDNA testing] is not something that international guidelines currently insist up – partly for that reason – so in the absence of sufficient funding treatment decision making in these patients will continue to be guided by histological characteristics.”
Related
Not all studies involving ctDNA surveillance are as positive, however.
A study published late last year in JAMA Network Open concluded that adding regular ctDNA testing to a nationally recommended imaging surveillance program for colorectal cancer had limited clinical benefits.
In this single-centre retrospective cohort study, 184 patients with stage II to stage IV colorectal cancer had a repeat ctDNA assay performed every three months for the first two years and then every six months for the following three years after curative-intent surgery.
“We [expected] the ctDNA assay to perform quite a bit better,” Professor Marwan Fakih, senior author on the paper, told Healio.
“Roughly a third of the patients – 14 out of 45 – had evidence of recurrence by imaging that ctDNA did not pick up. We expected that to occur for some patients, but we did not expect that it would be more than 30% of patients,” said the professor from the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Centre in California.
Only three patients (1.6% of individuals included in the study) remained disease free when data collection ceased despite the regular ctDNA and imaging surveillance.
“In my opinion, the 1.6% is an overestimation of the potential benefit you’re getting [from ctDNA]… it doesn’t mean that if you hadn’t done the ctDNA that you wouldn’t have continued to image those patients every 6 months as per [the National Comprehensive Cancer Network] guidelines. Perhaps you still would’ve found this tumour and had surgery that resulted in a curative outcome,” Fakih said.
“[But] at this point, this study tells us that the benefit of ctDNA surveillance resulting in a curative outcome is likely slim. It doesn’t mean that we shouldn’t be using it, but it also means that we should be careful in extrapolating from sensitivity from another country or another study.
“You will find some [recurrence] by ctDNA that you won’t find by imaging, and you’ll find some by imaging that you won’t find by ctDNA… It’s fair to say that the two tests are somewhat complementary if you want to catch as many recurrences as possible.”
