Colorectal
Eiji Oki, MD, PhD, FACS
Associate Professsor
Kyushu University
Fukuoka, Fukuoka, Japan
Disclosure: Bayer HealthCare Pharmaceuticals Inc. (Individual(s) Involved: Self): Advisor or Review Panel member, Speaker/Honoraria; Bristol Myers Squibb (Individual(s) Involved: Self): Speaker/Honoraria; CHUGAI PHARMACEUTICAL CO., LTD. (Individual(s) Involved: Self): Speaker/Honoraria; Eli Lilly (Individual(s) Involved: Self): Advisor or Review Panel member, Speaker/Honoraria; Guardant Health, Inc. (Individual(s) Involved: Self): Advisor or Review Panel member; ONO PHARMACEUTICAL CO., LTD. (Individual(s) Involved: Self): Speaker/Honoraria; TAIHO PHARMACEUTICAL CO., LTD (Individual(s) Involved: Self): Speaker/Honoraria; Takeda Pharmaceutical Co., Ltd. (Individual(s) Involved: Self): Speaker/Honoraria
Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) has the potential to identify patients who may benefit more from adjuvant chemotherapy (ACT) by predicting recurrence risk and can evaluate the efficacy of ACT by monitoring MRD dynamics.
Methods: A personalized tumor-informed assay (SignateraTM bespoke multiplex-PCR NGS assay) was used for the detection of ctDNA-based postsurgical MRD. Six-month disease-free survival (6M-DFS) rates were analyzed excluding patients enrolled in associated phase III trials (VEGA and ALTAIR).
Results: A total of 1,365 colorectal cancer patients (Stage I/II/III/IV:116/478/503/268) were enrolled between June 2020 and April 2021. MRD positivity rate at 4 weeks (4w-MRD+) was observed to be 15.9% (217/1,365) and was not different between laparoscopic and open surgery. However, patients with Clavien-Dindo Grade 2 or higher operative complication had significantly higher 4w-MRD+ rate (26.2% vs 15.8%, p=0.0018). 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). Of 1,365 patients, there were 188 patients with 4w-MRD+ and available MRD status at 12w; 95 patients received standard-of-care ACT per investigator’s decision. Cumulative incidence of ctDNA clearance was significantly higher in ACT vs. non-ACT (67% vs. 7% at 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 observed in all stages, including pStage II.
Conclusions: Our study demonstrated ctDNA dynamics during perioperative period and clearance associated with improved clinical outcomes in MRD+ patients. The study has shown that the patients can be stratified based on the ctDNA status, with MRD+ patients potentially showing benefit from ACT across all stages.