Controlled approaches using circulating tumor DNA can reduce the number of patients receiving adjuvant chemotherapy without the risk of reducing recurrence-free survival in some patients with stage II colon cancer.
Controlled approaches using circulating tumor DNA (ctDNA) may, according to the DYNAMIC Phase 2 study, reduce the number of patients receiving adjuvant chemotherapy without the risk of reducing recurrence-free survival in some patients with stage II colon cancer.1
“The strategy of using ctDNA results to inform treatment has reduced the number of patients who have undergone chemotherapy after surgery by almost half, from 28% to 15%. In patients with stage II colon cancer, ctDNA assessment after surgery allows for more accurate relapse prediction and patient selection for postoperative therapy, ”said lead author Jeanne Tie, MD, in a presentation of findings presented at ASCO at the 2022nd Annual Meeting and published in New England Journal of Medicine.1.2
The investigators randomized patients to the ctDNA-driven cohort (n = 294) or to the standard therapy cohort (n = 147). Those who tested negative for ctDNA in the controlled cohort were given the opportunity to give up chemotherapy, and those who tested 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 the decision was based on standard clinical factors (relative risk [RR], 1.82; 95% CI, 1.25-2.65).
Despite minor treatment in the ctDNA group, recurrence-free survival (RFS) was similar between the shoulders. Those in the ctDNA-driven cohort had a 2-year RFS rate of 93.5% compared to 92.4% in the standard treatment group (difference 1.1 percentage points; 95% CI, -4.1 to 6.2). The 3-year RFS rate was 91.7% and 92.4% (HR, 0.96; 95% CI, 0.51-1.82). In addition, the study found that patients with ctDNA-positive tumors had better outcomes when treated with oxaliplatin-based doublet compared to single-drug fluoropyrimidine therapy.
“Despite the lower proportion of patients receiving ctDNA-guided chemotherapy, they are more likely to be alive and cancer-free after 3 years, as with standard treatment,” said Tie, associate professor at the Walter and Eliza Hall Institute of Medical Research. and the Peter MacCallum Cancer Center in Victoria, Australia, said.
In a study conducted in Australia and New Zealand between 2015 and 2019, ctDNA analysis was completed in 99% of patients in the controlled arm (291 of 294). Two patients did not receive ctDNA-controlled treatment. There were 45 ctDNA positive patients in this group, all but 1 receiving chemotherapy. Chemotherapy was not administered to patients with ctDNA-negativity after surgery (n = 249), except for 1 patient.
The characteristics were balanced between the groups. The median age of the patients in the study was 64 years, with 27% 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%) and the remainder was T4. Other characteristics included poor tumor differentiation (14%), lymph node recovery less than 12 (5%), tumor perforation (3%), bowel obstruction (10%) and lymphovascular invasion (27%). Forty percent of patients were initially considered high risk.
In addition to avoiding chemotherapy in some patients, patients’ awareness that they were positive for ctDNA led to greater use of oxaliplatin-based doublet chemotherapy. In the ctDNA-driven group, 62% of patients received oxaliplatin-based doublets compared to only 10% in the standard arm. Single-acting fluoropyrimidine therapy was used in 90% of patients in the standard arm and in 38% of patients in the ctDNA-controlled group.
The median time from surgery to initiation of chemotherapy was longer in the ctDNA group, 83 days compared to 53 days in the standard group. The median duration of treatment in both groups was 24 weeks, and the primary reason for discontinuation was completion of scheduled treatment. The median 84% of patients in the standard arm received the full dose compared to 78% in the ctDNA group.
Less chemotherapy with a ctDNA-driven approach was used in all patient subgroups, except in patients with less than 12 lymph node yields and patients over 70 years of age who tended to receive less chemotherapy in the standard therapy arm. The largest difference in chemotherapy use, less preferred in the ctDNA-driven group, was in 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 controlled cohort, 6% of ctDNA-negative patients relapsed or died, compared with 18% in the ctDNA-positive group. The estimated 3-year RFS rate was 92.5% in ctDNA-negative patients who did not receive chemotherapy, compared with 86.4% in ctDNA-positive patients receiving chemotherapy (HR, 1.83; 95% CI, 0.79- 4.27). In addition, there was a difference in RFS according to the type of chemotherapy used in the ctDNA-positive group, with a 3-year RFS rate of 92.6% in patients receiving oxaliplatin-based doublets, compared to 76.0% in single-acting fluoropyrimidine therapy.
“Patients with a negative ctDNA result have a very low risk of relapse even though they do not receive chemotherapy, suggesting that postoperative therapy is unlikely to benefit this group of patients,” Tie said. “A ctDNA-driven approach can reduce the number of patients receiving chemotherapy without reducing their risk of relapse. Given the favorable outcome in ctDNA-positive patients receiving chemotherapy, this well-defined high-risk subgroup of patients is likely to benefit significantly from treatment. ”
Post-hoc data analysis attempted to combine clinical characteristics with ctDNA status to further refine therapy selection. In ctDNA-negative patients who did not receive chemotherapy, low-risk patients had a 3-year RFS rate of 96.7%, compared with 85.1% in patients with high-risk features (HR, 3.04; 95% CI, 1.26 – 7.34). Those with ctDNA-negative T3 tumors had a 3-year RFS rate of 94.2% compared to 81.3% in patients with T4 tumors (HR, 2.60 l 95% CI, 1.01-6.71).
“Liquid biopsies can be a useful tool for treatment decisions,” said ASCO expert Cathy Eng, MD, FACP, FASCO of the Vanderbilt-Ingram Cancer Center. “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 postoperative chemotherapy treatment and who could be spared further treatment without risking relapse. free survival. “
- Tie J, Cohen JD, Lahouel K et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: a randomized DYNAMIC study. J Clin Oncol. 2022; 40 (suppl 17): LBA100. doi: 10.1200 / JCO.2022.40.17_suppl.LBA100
- Tie J, Cohen JD, Lahouel K et al. Circulating tumor DNA analysis that controls stage II adjuvant therapy of colon cancer. N Engl J Med. Published online June 4, 2022. doi: 10.1056 / NEJMoa2200075
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