ctDNA demonstrates efficacy as a tool for treatment decisions for adjuvant chemotherapy in colon cancers

Guided approaches that use the DNA status of the circulating tumor may reduce the number of patients receiving adjuvant chemotherapy without the risk of a decrease in recurrence-free survival for some patients with stage II colon cancer.

Guided approaches using circulating tumor DNA (ctDNA) status may reduce the number of patients receiving adjuvant chemotherapy without the risk of lowering the 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 nearly halved the number of patients receiving chemotherapy after surgery, from 28% to 15%. In patients with stage II colon cancer, ctDNA assessment after surgery allows for more accurate prediction of relapse and patient selection for postoperative therapy,” said lead author Jeanne Tie, MD, in a presentation of the findings, which were presented at the 2022 ASCO Annual Meeting. and simultaneously published in the New England Journal of Medicine1.2

Researchers 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 opportunity to forgo chemotherapy and patients who tested positive for ctDNA received adjuvant chemotherapy. Overall, 15% of patients received chemotherapy in this arm compared to 28% in the standard treatment group, where 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, recurrence-free survival (RFS) between the arms were comparable. Those in the ctDNA-guided cohort had a 2-year RFS rate of 93.5% compared to 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). In addition, the study found that those with ctDNA-positive tumors experienced better outcomes when treated with an oxaliplatin-based doublet compared to a fluoropyrimidine monotherapy.

“Despite the lower percentage of patients receiving chemotherapy with ctDNA guidance, the odds of being alive and cancer-free after 3 years are the same as standard treatment,” said Tie, 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, 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 the exception of 1 who received chemotherapy. Chemotherapy was not administered to those with ctDNA negativity after surgery (n = 249), except in 1 patient.

Characteristics were equally distributed among the groups. The median age of patients in the study 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 on the left (46%) and right (54%) sides of the colon. The tumor stage was mainly T3 (85%) and the rest was T4. Other features were poor tumor differentiation (14%), lymph node yield less than 12 (5%), tumor perforation (3%), intestinal obstruction (10%) and lymphovascular invasion (27%). Forty percent of patients were considered 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-led group, 62% of patients received an oxaliplatin-based doublet versus only 10% in the standard arm. Fluoropyrimidine monotherapy was used for 90% of those in the standard arm and 38% of those in the ctDNA-guided group.

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

Less chemotherapy was used with the ctDNA-guided approach in all subgroups of patients, except those with less than 12 lymph node yield and those over 70 years of age, who tended to receive less chemotherapy in the standard therapy arm. The largest difference in chemotherapy use, in favor of 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, relapse or death occurred in 6% of patients with a ctDNA negative status compared to 18% of the ctDNA positive group. The estimated 3-year RFS rate was 92.5% in ctDNA negative patients not receiving chemotherapy compared to 86.4% in ctDNA positivity patients 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 of 92.6% for those receiving an oxaliplatin-based doublet compared to 76.0% for fluoropyrimidine monotherapy .

“Patients with a negative ctDNA result have a very low risk of relapse despite not receiving chemotherapy, suggesting that postoperative therapy is likely not beneficial for this group of patients,” Tie said. “The ctDNA-guided approach can reduce the number of patients treated with chemotherapy without compromising the risk of relapse. Given the favorable outcome in ctDNA-positive patients treated with chemotherapy, this well-defined subset of high-risk patients is likely to benefit significantly from treatment.”

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

“Liquid biopsies can be a useful tool in guiding treatment decisions,” ASCO expert Cathy Eng, MD, FACP, FASCO of 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 stage II colorectal cancer patients would benefit from postoperative chemotherapy and which could be spared the additional treatment, without jeopardizing relapse. survive freely.”

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. DNA analysis of circulating tumors as a guideline for adjuvant therapy in stage II colorectal cancer. N Engl J Med† Published online June 4, 2022. doi:10.1056/NEJMoa2200075

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