ctDNA demonstrates its effectiveness as a treatment decision tool for adjuvant chemotherapy in colon cancers

According to results from the DYNAMIC Phase 2 study, guided approaches leveraging circulating tumor DNA (ctDNA) status can reduce the number of patients who receive adjuvant chemotherapy without risking reduced disease-free survival rates for some patients with stage II colon cancer.¹

“The strategy of using ctDNA results to inform treatment nearly halved the number of patients who received post-operative chemotherapy, from 28% to 15%. In patients with stage II colon cancer, post-surgery cDNA assessment allows for more accurate prediction of relapse and patient selection for post-surgical treatment,” said the author. Principal Jeanne Tie, MD, in a presentation of the results, which were presented at the ASCO 2022 Annual Meeting and simultaneously published in the New England Journal of Medicine.^1.2

Investigators randomly assigned patients to either a ctDNA-guided treatment cohort (n=294) or a standard treatment cohort (n=147). Those who tested negative for ctDNA in the guided cohort were given the option of forgoing chemotherapy, and patients who tested positive for ctDNA received adjuvant chemotherapy. Overall, 15% of patients received chemotherapy in this arm versus 28% in the standard treatment group, in which the 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, disease-free survival (RFS) rates were similar between the arms. Those in the ctDNA-guided cohort had a 2-year RFS rate of 93.5% versus 92.4% in the standard treatment group (difference of 1.1 percentage points; 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 people with ctDNA-positive tumors had better outcomes when treated with oxaliplatin-based doublet therapy compared to single-agent fluoropyrimidine therapy.

“Despite the lower proportion of patients receiving chemotherapy with ctDNA guidance, the probability of being alive and cancer-free at 3 years is the same as standard management,” said Tie, associate professor at 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, cDNA analysis was performed for 99% of people in the guided arm (291 out of 294). Two patients did not receive ctDNA-guided treatment. In this group, 45 patients were ctDNA positive, with all but 1 receiving chemotherapy. Chemotherapy was not given to people with negative ctDNA after surgery (n = 249), except for one patient.

Characteristics were also matched between groups. The median age of study patients was 64 years, with 27% being over 70 years of age. The most common ECOG performance status was 0 (80%) and tumors were evenly distributed between left (46%) and right (54). %) sides of the colon. The tumor stage was mainly T3 (85%), the rest being T4. Other features included low 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, knowledge that patients were ctDNA positive has led to increased use of dual oxaliplatin-based chemotherapy. In the ctDNA-guided group, 62% of patients received an oxaliplatin-based doublet versus only 10% in the standard arm. Fluoropyrimidine monotherapy treatment was used for 90% of patients in the standard group and for 38% of those in the ctDNA-guided group.

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

There was less chemotherapy used with the ctDNA-guided approach in all patient subgroups except those with lymph node yields below 12 and those over 70, who tended to receive less chemotherapy in the standard treatment arm. The greatest difference in chemotherapy use, favoring less in the ctDNA-guided group, was in patients with T4 tumors (RR, 2.57; 95% CI, 1.46-4.50) , high-risk features (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 versus 18% of the ctDNA-positive group. The estimated 3-year RFS rate was 92.5% in patients in the ctDNA-negative group who did not receive chemotherapy, compared to 86.4% in tcDNA-positive patients treated with chemotherapy (HR, 1.83 95% CI, 0.79-4.27). Additionally, there was a difference in RFS by type of chemotherapy used in the ctDNA-positive group, with a 3-year RFS rate of 92.6% for those receiving an oxaliplatin-based doublet versus 76 .0% for fluoropyrimidine monotherapy therapy.

“Patients with a negative cDNA result have a very low risk of relapse, even if they do not receive chemotherapy, suggesting that postoperative treatment is unlikely to benefit this group of patients. patients,” Tie said. “The ctDNA-guided approach can reduce the number of patients treated with chemotherapy, without compromising their risk of relapse. Given the favorable outcomes in ctDNA-positive patients treated with chemotherapy, this well-defined subgroup of high-risk patients will likely derive substantial benefit from treatment.

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 low clinical risk features had a 3-year RFS rate of 96.7% compared to 85.1% in those with low clinical risk features. at high risk (HR, 3.04; 95% CI, 1.26-7.34). People with T3 tumors with negative ctDNA status had a 3-year RFS rate of 94.2% versus 81.3% in those with T4 tumors (HR, 2.60l 95% CI, 1.01- 6.71).

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

References

1. Tie J, Cohen JD, Lahouel K, et al. Adjuvant chemotherapy guided by analysis of circulating tumor DNA in stage II colon cancer: the DYNAMIC randomized trial. J Clin Oncol. 2022;40(supplement 17):LBA100. doi:10.1200/JCO.2022.40.17_suppl.LBA100
2. Tie J, Cohen JD, Lahouel K, et al. Analysis of circulating tumor DNA guiding adjuvant therapy in stage II colon cancer. N English J med. Published online June 4, 2022. doi:10.1056/NEJMoa2200075