Utilization of ctDNA Assays Could Determine Benefit of Adjuvant Chemotherapy in Resectable CRC

The use of circulating tumor (ct)DNA assays may help identify patients with colorectal cancer who could benefit from adjuvant chemotherapy, according to data from the observational GALAXY trial (UMIN000039205), which were presented at the 2022 Gastrointestinal Cancer Symposium.

Patients with high-risk stage II disease and ctDNA-positive status at 4 weeks experienced a 6-month DFS rate of 100% (95% CI, 100%-100%) with adjuvant chemotherapy vs 53.8% (95% CI, 24.8%-76.0%) without. In stage III disease, those rates were 89.2% (95% CI, 78.7%-94.7%) and 32.0% (95% CI, 15.2-50.2), respectively. For stage IV disease, adjuvant chemotherapy use in patients with positive ctDNA status resulted in 6-month DFS rates of 72.7% (95% CI, 49.1%-86.7%) vs 28.3% (95% CI, 16.2-41.6) for those without.

“Our study shows that stratifying post-surgical treatment decisions using the assay can identify patients likely to benefit from ACT [adjuvant chemotherapy] across all stages,” Masahito Kotaka, MD, PhD, from Gastrointestinal Cancer Center, Sano Hospital, said during the presentation.

This study that is a part of the CIRCULATE-Japan platform protocol in patients with resectable CRC was undertaken to determine if ctDNA-based molecular residual disease (MRD) status could be a viable risk-assessment strategy for adjuvant therapy selection post-surgery. Personalized tumor-informed ctDNA assays were collected at 4, 12, 24, 36, 48, 72, and 96 weeks after surgery.

A total of 1564 patients were enrolled to GALAXY between June 5, 2020, and April 30, 2021, of whom 1040 were included in the current analysis (Outcome cohort). After excluding ineligible patients, investigators further divided the cohorts into patients who were ctDNA positive (n = 183), known as the Clearance cohort, and ctDNA negative (n = 531) 4-weeks post-surgery.

The Outcome cohort was majority male in both the positive and negative groups (51% vs 62%; P < .01), with stage III cancer occurring most frequently (36% vs 48%). Patients with negative vs positive ctDNA were more likely to harbor BRAF V600E mutations (9% vs 3%; P < .01) or have microsatellite instability (MSI)–high tumors (12% vs 3%; P < .001). The Clearance analysis cohort was majority male (54% vs 72%; P = .01) with stage III (68% vs 29%; P <.001) or stage IV (23% vs 53%; P < .001) cancer in patients who received adjuvant chemotherapy versus those who did not, respectively. Only 1 patient had stage I and 2 patients had low-risk stage II disease along with ctDNA-positive status.

With a median follow-up of 11.4 months in the overall population of patients with stage I to IV disease, 6- and 12-month disease-free survival (DFS) rates were 96.5% (95% CI, 95.0%-97.5%) and 92.7% (95% CI, 90.4%-94.5%) for those with ctDNA-negative status 4-weeks post-operative. Those with ctDNA positivity had significantly worse outcomes, with corresponding DFS rates of 62.8% (95% CI, 55.4%-69.2%) and 47.5% (95% CI, 39.3%-55.2%; HR, 10.9; 95% CI, 7.8-15.4; P < .001; sensitivity for recurrence, 63.6%). Limiting the analysis to patients with stage II to IV disease indicated that 6- and 12-month rates of DFS favored the negative vs positive cohorts at 97.8% (95% CI, 96.3%-98.7%) vs 73.0% (95% CI, 63.9%-80.2%) and 95.2% (95% CI, 92.6%-96.9%) vs 55.5% (95% CI, 44.8%-65.0%), respectively (HR, 13.3; 95% CI, 8.0-22.2; P < .001; sensitivity for recurrence 67.6%).

The multivariate analysis found that the highest risk of recurrence for patients with stage II to III cancer was correlated with 4-weeks post-surgery ctDNA positive vs negative status (HR, 15.3; 95% CI, 8.6-27.2; P < .001), mutant vs wild-type RAS (HR, 1.8; 95% CI, 1.0-3.1; P = .04), or mutant vs wild-type BRAF (HR, 5.2; 95% CI, 2.1-12.9; P < .001).

Investigators then performed an analysis which excluded patients who recurred within 12 weeks of surgery, called the Dyanmics analysis cohort (n = 838), to evaluate the predictive effect of ctDNA on this population. The 6-month DFS rate for those with ctDNA-negative status at the 4-week time point and negative status at the 12-week point was 100% vs 98.0% with negative/negative ctDNA (HR, 0.8; 95% CI, 0.27-2.15; P = .60), 62.5% for negative to positive ctDNA (HR, 9.2; 95% CI, 3.0%-28.4%; P < .001), and 58.3% for positive/positive (HR, 15.8; 95% CI, 5.7%-44.2%; P < .001).

Cumulative clearance of ctDNA at 6 months after surgery was higher amongst those who received adjuvant chemotherapy vs no chemotherapy, at rates of 68% vs 10%, respectively (HR, 9.3; 95% CI, 4.6-18.9; P <.001). A multivariate analysis of patients with stage II to IV disease showed the risk of recurrence was significantly between those with and without adjuvant chemotherapy (HR, 5.6; 95% CI, 3.2-9.7; P < .001) and RAS mutant vs wild-type status (HR, 2.0; 95% CI, 1.3-3.1; P = .03).

The 12-month DFS rate for those who received adjuvant chemotherapy and had high-risk stage II cancer was 88.9% (95% CI, 43.3%-98.4%) vs 46.2% without (95% CI, 19.2-69.6%; HR, 9.4; 95% CI, 1.1-79.1; P = .04). In stage III disease, the 12-month DFS rates were 68.3% (95% CI, 53.4%-79.2%) vs 24.0% (95% CI, 9.8%-41.7%), respectively (HR, 8.8; 95% CI, 3.9-19.5; P <.001). For stage IV, corresponding rates were 53.7% (95% CI, 28.4%-73.6%) vs 22.3% (95% CI, 11.2%-35.7%; HR, 2.4; 95% CI, 1.1-5.2; P = . 02).

In the ctDNA-negative cohort treated with adjuvant vs no chemotherapy, patients were 50% male, had performance status of 0 (92% vs 81%, respectively; P = .001), and had stage III cancer (83% vs 41%; P <.001). Those treated with adjuvant chemotherapy had 6- and 12-month DFS rates of 98.6% (95% CI, 95.7%-99.5%) and 96.2% (95% CI, 92.1%-98.2%) compared with 97.5% (95% CI, 95.0%-98.7%) and 94.7% (95% CI, 90.5%-97.1%) for those with chemotherapy (HR, 1.3; 95% CI, 0.5-3.6; P = .63).

“ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented in the future conferences,” Kotaka concluded.

Reference

1. Kataka M, Shirasu H, Wantanbe J, et al. Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-Japan. J Clin Oncol. 2022;40(suppl 4):9. 10.1200/JCO.2022.40.4_suppl.009