ctDNA Demonstrates Efficacy as Treatment-Decision Tool for Adjuvant Chemotherapy in Colon Cancers

Jeanne Tie, MD

Guided approaches leveraging circulating tumor DNA (ctDNA) status can reduce the number of patients who receive adjuvant chemotherapy without the risk of lowering recurrence-free survival rates for some patients with stage II colon cancer, according to findings from the phase 2 DYNAMIC study.¹

“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy post-surgery, from 28% down to 15%. In stage II colon cancer patients, ctDNA assessment after surgery allows a more precise prediction of relapse and patient selection for post-surgical therapy,” lead author Jeanne Tie, MD, said in a presentation of the findings, which were presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.^1,2

Investigators randomly assigned patients to ctDNA-guided treatment cohort (n = 294) or a standard-therapy cohort (n = 147). Those who tested negative for ctDNA in the guided cohort were given the chance to forego chemotherapy and patients who were positive for ctDNA received adjuvant chemotherapy. Overall, 15% of patients received chemotherapy in this arm compared with 28% in the standard-treatment group, in which decision was based on standard clinical factors (relative risk [RR], 1.82; 95% CI, 1.25-2.65).

Despite less treatment in the ctDNA group, the recurrence-free survival (RFS) rates were similar between arms. Those in the ctDNA-guided cohort had a 2-year RFS rate of 93.5% compared with 92.4% in the standard treatment group (1.1 percentage point difference; 95% CI, –4.1 to 6.2). The 3-year RFS rates were 91.7% and 92.4%, respectively (HR, 0.96; 95% CI, 0.51-1.82). Additionally, the study found that those with ctDNA-positive tumors experienced better outcomes when treated with an oxaliplatin-based doublet compared with a single-agent fluoropyrimidine therapy.

“Despite the lower proportion of patients receiving chemotherapy with ctDNA guidance, the likelihood of being alive and cancer free at 3 years is the same as the standard management,” Tie, who is an associate professor at the Walter and Eliza Hall Institute of Medical Research and Peter MacCallum Cancer Center in Victoria, Australia, said.

In the study, which was conducted in Australia and New Zealand between 2015 and 2019, ctDNA analysis was completed for 99% of those in the guided arm (291 of 294). Two patients did not receive ctDNA-guided treatment. In this group, 45 patients were ctDNA-positive, with all except 1 receiving chemotherapy. Chemotherapy was not administered to those with ctDNA-negativity following surgery (n = 249), except for 1 patient.

Characteristics were evenly matched across groups. The median age of patients in the study was 64 years, with 27% being over the age of 70. The most common ECOG performance status was 0 (80%) and tumors were evenly distributed between the left (46%) and right (54%) sides of the colon. The tumor stage was primarily T3 (85%) with the remainder being T4. Other characteristics included poor tumor differentiation (14%), lymph node yield less than 12 (5%), tumor perforation (3%), bowel obstruction (10%), and lymphovascular invasion (27%). Forty percent of patients were deemed high risk at baseline.

In addition to avoiding chemotherapy in some patients, knowing patients were ctDNA-positive resulted in greater use of an oxaliplatin-based doublet chemotherapy. In the ctDNA-guided group, 62% of patients received an oxaliplatin-based doublet vs just 10% in the standard arm. A single-agent fluoropyrimidine therapy was used for 90% of those in the standard arm and for 38% of those in the ctDNA-guided group.

The median time from surgery to start of chemotherapy was longer in the ctDNA group, at 83 days compared with 53 in the standard group. The median treatment duration was 24 weeks in both groups and the primary cause for discontinuation was completion of planned treatment. A median of 84% of patients in the standard arm received the full dose compared with 78% in the ctDNA group.

There was less chemotherapy used with the ctDNA-guided approach across all patient subgroups, except for those with less than 12 lymph node yield and those over the age of 70, who tended to receive less chemotherapy in the standard therapy arm. The biggest difference in chemotherapy use, favoring less in the ctDNA-guided group, was for patients with T4 tumors (RR, 2.57; 95% CI, 1.46-4.50), high-risk characteristics (RR, 2.14; 95% CI, 1.43-3.21), and poorly differentiated tumors (RR, 5.06; 95 CI, 1.02-25.10).

In the guided cohort, recurrence or death occurred in 6% of patients with ctDNA-negative status compared with 18% of the ctDNA-positive group. The estimated 3-year RFS rate was 92.5% in patients from the ctDNA-negative group who did not receive chemotherapy compared with 86.4% in patients with ctDNA positivity treated with chemotherapy (HR, 1.83; 95% CI, 0.79-4.27). Furthermore, there was a difference in RFS by type of chemotherapy used within the ctDNA-positive group, with a 3-year RFS rate of 92.6% for those receiving an oxaliplatin-based doublet compared with 76.0% for single-agent fluoropyrimidine therapy.

“Patients with a negative ctDNA result have a very low risk of relapse, despite not receiving chemotherapy, suggesting post-surgery therapy is unlikely to benefit this group of patients,” Tie said. “The ctDNA-guided approach can reduce the number of patients treated with chemotherapy, without compromising their relapse risk. Given the favorable outcome in ctDNA-positive patients treated with chemotherapy, this well-defined high-risk subgroup of patients will likely derive substantial benefit from treatment.”

A post-hoc analysis of the data attempted to combine clinical characteristics with ctDNA status to further refine therapy selection. In patients with ctDNA negativity who did not receive chemotherapy, those with clinically low-risk characteristics had a 3-year RFS rate of 96.7% compared with 85.1% in those with high-risk features (HR, 3.04; 95% CI, 1.26-7.34). Those with T3 tumors with ctDNA-negative status had a 3-year RFS rate of 94.2% compared with 81.3% in those with T4 tumors (HR, 2.60l 95% CI, 1.01-6.71).

“Liquid biopsies can be a useful tool for guiding treatment decisions,” ASCO Expert Cathy Eng, MD, FACP, FASCO, from the Vanderbilt-Ingram Cancer Center, said in a statement. “Thanks to the results of this study, we may now be able to use it to better identify which patient with stage II colon cancer would benefit from post-surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival.”

References

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. J Clin Oncol. 2022;40(suppl 17):LBA100. doi:10.1200/JCO.2022.40.17_suppl.LBA100
2. Tie J, Cohen JD, Lahouel K, et al. Circulating tumor dna analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. Published online June 4, 2022. doi:10.1056/NEJMoa2200075