Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer

Abstract

Background: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.

Methods: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.

Results: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.

Conclusions: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Figure 1.. Receipt of Adjuvant Chemotherapy in the Intention-to-Treat Population According to Subgroup.

The relative risk and 95% confidence intervals for the receipt of adjuvant chemotherapy in the standard-management group as compared with the circulating tumor DNA (ctDNA)–guided group are shown. The intention-to-treat population included all eligible patients who underwent randomization and had both week 4 and week 7 postsurgical blood specimens. The size of each square corresponds to the size of the subgroup. For the subgroup with poorly differentiated tumors, the relative risk lies beyond the upper limit of the horizontal axis and is not shown.

Figure 2.. Outcomes with ctDNA-Guided as Compared with Standard Management in the Intention-to-Treat Population.

Panel A shows the absolute difference in recurrence-free survival over time between the ctDNA-guided and standard-management groups; shading indicates the 95% confidence interval. The noninferiority margin of −8.5 percentage points for the primary end point of recurrence-free survival at 2 years is indicated by the dashed red line; the 𝙸 bar indicates the 95% confidence interval at 2 years, the lower bound of which (−4.1 percentage points) lies above −8.5 percentage points, which confirms noninferiority of ctDNA-guided management to standard management. Kaplan–Meier estimates of recurrence-free survival according to the assigned management group are shown in Panel B. Tick marks indicate censored data. At 3 years, 91.7% of the patients in the ctDNA-guided group and 92.4% of those in the standard-management group were alive without disease recurrence.

Figure 3.. Recurrence-free Survival in the ctDNA-Guided Group According to ctDNA Status.

Kaplan–Meier estimates of recurrence-free survival according to ctDNA result (positive or negative) are shown. The 3-year recurrence-free survival was 92.5% among ctDNA-negative patients who did not receive adjuvant chemotherapy and 86.4% among ctDNA-positive patients who received adjuvant chemotherapy. Tick marks indicate censored data.