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.
Authors: Masahito Kotaka, Hiromichi Shirasu, Jun Watanabe, Kentaro Yamazaki, Keiji Hirata, Naoya Akazawa, Nobuhisa Matsuhashi, Mitsuru Yokota, Masataka Ikeda, Kentaro Kato, Alexey Aleshin, Shruti Sharma, Daisuke Kotani, Eiji Oki, Ichiro Takemasa, Takeshi Kato, Yoshiaki Nakamura, Hiroya Taniguchi, Masaki Mori, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2022)

9 Background: Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) has the potential to select patients who may benefit more from standard-of-care (SOC) adjuvant chemotherapy (ACT) by accurately assessing recurrence-risk post-surgery and by evaluating ACT efficacy. Here we present an analysis from GALAXY study, an observational study monitoring MRD, to evaluating the association of ctDNA dynamics with a short-term clinical outcome and ACT efficacy. Methods: A personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) was used for post-surgical MRD detection in colorectal cancer (CRC) patients. Six-month disease-free survival (6M-DFS) rates were analyzed excluding patients enrolled in associated phase III trials (VEGA and ALTAIR). Results: Total 1,365 CRC patients enrolled between June 2020 and April 2021 were included in this analysis; 116 pStage I, 478 pStage II, 503 pStage III, and 268 oligomet resectable pStage IV (16% [42/268] received neoadjuvant chemotherapy). 6M-DFS rate by ctDNA dynamics from 4w to 12w were 98% in ‘negative to negative’ group (N = 618), 59% in ‘negative to positive’ (N = 32), 100% in ‘positive to negative’ (N = 58), and 45% in ‘positive to positive’ (N = 78), with a significant difference between ‘positive to negative’ and ‘positive to positive’ groups with hazard ratio (HR) of 52.3 (95% CI: 7.2-380.5; p &lt; 0.001), with a median follow-up time of 6.6 months. Further, out of 188 patients who were MRD+ at 4w with available MRD status at 12w, 95 received SOC ACT (80/95 received fluoropyrimidine [FP] + oxaliplatin and 15 received FP alone) by an investigator’s decision. ctDNA clearance rate at 12w was significantly higher in ACT vs. non-ACT; 57% (54/95) vs. 8% (7/93) in pStage I-IV (p &lt; 0.001), and 58% (42/72) vs. 11% (4/37) in pStage II-III (p &lt; 0.001). In addition, ctDNA clearance rate at 24w was also significantly higher in ACT vs. non-ACT; 26% (7/27) vs. 0% (0/30) in pStage I-IV (p = 0.003), and 33% (7/21) vs. 0% (0/15) in pStage II-III (p = 0.03). Cumulative incidence of ctDNA clearance was significantly higher in ACT vs. non-ACT (67% vs. 7% by 24w; cumulative HR = 17.1; 95% CI: 6.7-43.4, p &lt; 0.001). Among 4w-MRD+ patients, 6M-DFS rate was significantly higher in ACT vs. non-ACT; 84% vs. 34% (HR = 0.15; 95% CI: 0.078-0.25; p &lt; 0.001), which was seen in all stages, including pStage II. Conclusions: This analysis from the GALAXY study, is the largest MRD study to date, demonstrating the association of ctDNA dynamics with improved clinical outcomes in MRD+ patients. Our study shows that stratifying post-surgical treatment decisions using the assay can identify patients likely to benefit from ACT across all stages, including pStage II. ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented in the future conferences. Clinical trial information: jRCT1031200006.