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

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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 < 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 < 0.001), and 58% (42/72) vs. 11% (4/37) in pStage II-III (p < 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 < 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 < 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.