The use of postoperative circulating tumor DNA (ctDNA) in stage II colon cancer spared many patients the need for adjuvant chemotherapy without compromising recurrence-free survival, according to the phase II DYNAMIC study.1
Jeanne Tie, MD, FRACP, MBChB
“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy after surgery, from 28% to 15%, and the chance of being alive and cancer-free at 3 years was comparable,” said Jeanne Tie, MD, FRACP, MBChB, Associate Professor at the Walter and Eliza Hall Institute of Medical Research and Peter MacCallum Cancer Centre, Victoria, Australia. Dr. Tie presented the findings at the 2022 ASCO Annual Meeting.1 The study was simultaneously published in The New England Journal of Medicine.2
Study Rationale and Methodology
Surgery alone can cure more than 80% of cases of stage II colon cancer. However, the benefit of chemotherapy after surgery is unclear, though it is often recommended for patients with high-risk tumor features.
“More precise prediction of relapse risk may help limit treatment to very high–risk patients who are most likely to benefit and avoid unnecessary treatment in low-risk patients who are not,” said Dr. Tie. “A ctDNA blood test can identify patients who have microscopic cancer remaining after surgery. These patients have a very high chance—more than 80%—of cancer relapse if left untreated.”
The phase II DYNAMIC trial was conducted in Australia between 2015 and 2019 using the Safe-SeqS tumor-informed personalized ctDNA assay. Patients were randomly assigned 2:1 to have their disease managed according to ctDNA results (ctDNA-guided management; n = 294) or by the treating clinician according to standard clinicopathologic criteria (standard management; n = 147).
In the ctDNA-guided arm, patients with a positive ctDNA result at either week 4 or 7 received adjuvant single-agent fluoropyrimidine or oxaliplatin-based chemotherapy. Patients with negative ctDNA results at both time points were not treated with adjuvant chemotherapy.
Characteristics were evenly matched across groups. Overall, the median patient age was 64 years; 46% of patients had left-sided tumors, and 54% had right-sided tumors; 85% had tumor stage T3 disease; and 40% were deemed to be at high risk at baseline.
The primary efficacy endpoint was recurrence-free survival at 2 years, calculated from the date of randomization. Median follow-up was 37 months.
In the ctDNA-guided treatment arm, the rate of recurrence-free survival was 92.5% among those who did not receive adjuvant therapy—the same as the rate of recurrence-free survival in the standard management arm. Also in the ctDNA-guided treatment arm, recurrent disease was observed at 3 years among 7% of -ctDNA-negative patients who did not receive adjuvant chemotherapy, as compared with 14% of ctDNA-positive patients who were treated with chemotherapy (hazard ratio [HR] = 2.45; 95% confidence interval [CI] = 1.00–5.99).
“For patients with stage II colon cancer, a ctDNA-guided approach that treats only patients with detectable ctDNA after surgery substantially reduced the use of adjuvant chemotherapy and did not compromise recurrence-free survival. Additionally, the favorable 3-year recurrence-free survival seen in ctDNA--positive patients treated with adjuvant chemotherapy compared with previously reported low recurrence-free survival in untreated patients, suggesting a benefit may be gained from adjuvant chemotherapy in this well-defined, high-risk subgroup,” Dr. Tie said.
Chemotherapy was delivered to 15% of the ctDNA-guided arm vs 28% of the standard-management arm (relative risk = 1.82; 95% CI = 1.25–2.65). For patients with high-risk clinicopathologic features, the likelihood of receiving adjuvant -chemotherapy was more than twice as high in the standard-management group as in the ctDNA-guided group. Among all patients who received adjuvant chemotherapy, an oxaliplatin-based doublet (vs single-agent fluoropyrimidine) was administered to a higher percentage of the ctDNA-guided group than of the standard-management group (62% vs 10%). Almost all (90%) of the chemotherapy administered under standard management was single-agent fluoropyrimidine.
The type of treatment seemed important, at least for -ctDNA-positive patients. They had better recurrence-free survival at 3 years after receiving an oxaliplatin-based doublet (92.6%) than single-agent fluoropyrimidine (76.0%).
The percentages of patients surviving without disease recurrence at 2 years and at 3 years were similar in the ctDNA-guided group and the standard-management group: 2-year recurrence-free survival was 93.5% and 92.4%, respectively; 3-year recurrence-free survival was 91.7% and 92.4%, respectively. These data confirmed noninferiority of the ctDNA-guided approach, said Dr. Tie.
“We also confirmed a very low recurrence risk in untreated ctDNA-negative patients, most notably in those with clinical low-risk disease and T3 tumors,” she added.
Regarding outcomes in the ctDNA-guided group according to ctDNA status, more ctDNA-positive patients recurred or died (18%) than ctDNA-negative patients (6%). Their estimated 3-year recurrence-free survival was 86.4% vs 92.5%, respectively (HR = 1.83; 95% CI = 0.79–4.27); the percentage with a recurrence at 3 years was 14% vs 7%, respectively (HR = 2.45; 95% CI = 1.00–5.99).
Study co-investigator Cristian Tomasetti, PhD, now Director of the Center for Cancer Prevention and Early Detection at City of Hope, offered these comments on the DYNAMIC trial: “These results are exciting
Cristian Tomasetti, PhD
because they can make a difference in patients’ lives and are convincing enough to have a major impact on physicians in the community, who could certainly use this test to guide treatment in stage II colorectal cancer.”
“An important issue now is the need to quickly scale up the availability of this test for the general community. This will happen, hopefully, soon enough, and we are not too far away from a time when these types of tests will be available for many cancer types at different stages, not just colorectal cancer at stage II,” Dr. Tomasetti predicted.
DISCLOSURE: Dr. Tie has received honoraria from or served as a consultant or advisor to Inivata, Servier, AstraZeneca/MedImmune, Bristol Myers Squibb, Haystack Oncology, MSD Oncology, and Pierre Fabre. Dr. Tomasetti reported no conflicts of interest.
1. Tie J, Cohen JD, Lahouel K, et al: Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: The randomized DYNAMIC trial. 2022 ASCO Annual Meeting. Abstract LBA100. Presented June 4, 2022.
Ben Ho Park, MD, PhD
The invited discussant of the DYNAMIC study was Ben Ho Park, MD, PhD, who said the study “has really moved the needle for circulating tumor DNA [ctDNA] analysis and guiding therapy.” Dr. Park is Director of the Vanderbilt-Ingram Cancer Center, Nashville.