Postoperative Circulating Tumor DNA Monitoring in Stage I-III Driver-Mutant Colon Adenocarcinoma (ADX-DRIVER-CRC)

Multicenter Prospective Cohort Study of Molecular Residual Disease (MRD) in Stage I-III Surgically Resectable Colon Adenocarcinoma Harboring Oncogenic Driver Mutations

This multicenter prospective observational cohort study will enroll 392 patients with stage I-III colon adenocarcinoma who undergo curative resection and whose tumors harbor at least one prespecified oncogenic driver mutation (KRAS, NRAS, BRAF, or PIK3CA). Serial plasma circulating tumor DNA (ctDNA) testing for molecular residual disease (MRD) will be performed with a standardized 10-gene next-generation sequencing (NGS) panel at predefined time points during 3 years of postoperative follow-up. The primary objective is to evaluate the association between postoperative ctDNA-based MRD status and recurrence-free survival (RFS). Secondary objectives include evaluating overall survival (OS), the interval between first MRD detection and radiologically confirmed recurrence, and the association between longitudinal MRD changes and outcomes following adjuvant chemotherapy.

Study Overview

• Status: Recruiting
• Conditions: Stage I Colon Cancer; Stage II Colon Cancer; Stage III Colon Cancer; Colon Adenocarcinoma
• Intervention / Treatment: Other: Longitudinal ctDNA-MRD NGS testing at scheduled postoperative time points

Detailed Description

Background Colorectal cancer (CRC) ranks the 3rd most common malignancy worldwide and the 2nd leading cause of cancer death. In China, CRC incidence and mortality keep rapidly rising, with ~517,000 new cases and ~240,000 deaths annually. Radical resection is the curative standard for stage I-III CRC, yet postoperative recurrence reaches 20%-40% even after microscopically margin-negative (R0) resection. Traditional tumor-node-metastasis (TNM) staging and clinicopathological features fail to precisely stratify recurrence risk within the same stage, lacking capacity for early, real-time recurrence surveillance. Oncogenic driver mutations (KRAS, NRAS, BRAF, PIK3CA) dominate colorectal tumorigenesis and correlate with higher recurrence risk and worse prognosis, but static mutation status cannot reflect dynamic postoperative residual tumor burden. Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) enables non-invasive early detection of microscopic residual tumor, predicting recurrence months prior to radiological abnormalities, with strong prognostic value validated by multiple landmark trials. However, nearly all existing MRD cohorts lack stratification by driver mutation status; large-scale prospective multicenter data focusing exclusively on driver-mutant stage I-III colon adenocarcinoma are absent globally. This study fills the clinical gap by combining driver genotyping and longitudinal ctDNA-based MRD surveillance.

Scientific Hypothesis In patients with driver-mutant stage I-III resectable colon adenocarcinoma, postoperative ctDNA-based MRD status acts as an independent prognostic biomarker for recurrence regardless of conventional clinicopathological factors. Dynamic serial MRD shifts can alert tumor relapse earlier than routine contrast-enhanced computed tomography (CT), and different driver mutation subtypes demonstrate heterogeneous MRD detectability and predictive efficacy. Persistent MRD positivity predicts high recurrence risk, while sustained MRD negativity indicates excellent prognosis and potential de-escalation of adjuvant chemotherapy.

Study Design & Procedures A total of 10 tertiary hospitals with colorectal surgery and molecular pathology capacity will consecutively enroll eligible patients within 1 year. All participants receive standardized perioperative and follow-up care per clinical guidelines without study-mandated intervention modification. Serial peripheral blood samples (20 mL per draw) are collected at fixed time points: pre-operation (T0, baseline), postoperative day 7±2 (T1), 1 month post-surgery before adjuvant chemotherapy (T2), every 3 months up to 12 months (T3-T6), every 6 months at 18/24 months (T7-T8), and 36 months post-operation (T9). ctDNA-based MRD testing is performed centrally by Amoy Diagnostics using a fixed 10-gene next-generation sequencing (NGS) panel covering all core CRC driver mutations, sequencing depth ≥100,000×. MRD positivity is defined as detection of any tumor-derived driver mutation in plasma at any postoperative time point. All patients receive standardized 3-year follow-up: physical exam + tumor markers every 3 months in year 1; every 6 months in year 2; annual follow-up in year 3. Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis is conducted every 6 months, colonoscopy at 12, 24 and 36 months postoperatively. All recurrence events are adjudicated by an blinded independent central review (BICR).

Statistical Plan Primary analysis uses Kaplan-Meier curves and log-rank test to compare RFS between MRD-positive and MRD-negative groups; multivariate Cox proportional hazards regression adjusts for age, sex, TNM stage, differentiation grade, adjuvant chemotherapy regimen and driver mutation subtype to confirm MRD as independent prognostic factor. Secondary endpoints including OS, 1- and 2-year RFS rates, median lead time of MRD ahead of radiological recurrence are analyzed via survival statistics. All statistical tests are two-sided with α=0.05, analyzed using R 4.3.0 and SPSS software. Sample size calculation accounts for 20% dropout rate, targeting total enrollment of 392 patients to ensure statistical power of 0.95 for primary endpoint analysis.

• Study Type: Observational
• Enrollment (Estimated): 392

Contacts and Locations

• Study Contact: Name: Ren Zhao, MD, PhD; Phone Number: +86 18917762018; Email: zhaorensurgeon@aliyun.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201801
      • Recruiting
      • Ruijin Hospital North
      • Contact: Kun Liu, MD; Phone Number: 18121263082; Email: lookiere@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients will be selected from consecutive adults evaluated for curative-intent surgery for pathologically confirmed stage I-III colon adenocarcinoma at 10 participating tertiary hospitals in China with colorectal surgery and molecular pathology capabilities. The study cohort will include eligible patients aged 18-75 years whose tumor tissue harbors at least one prespecified oncogenic driver mutation and who consent to serial postoperative blood collection and 3 years of follow-up.

Description

Inclusion Criteria:

1. Age 18-75 years, regardless of sex
2. Pathologically confirmed colon adenocarcinoma, clinical stage I-III without preoperative endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR)
3. Planned curative surgical resection, no prior anti-tumor therapy (chemotherapy, radiotherapy, targeted therapy) before surgery
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
5. Tumor tissue positive for at least one driver mutation among KRAS, NRAS, BRAF, PIK3CA
6. Voluntary participation with signed written informed consent, good compliance with scheduled follow-up and blood collection.

Exclusion Criteria:

1. Received neoadjuvant chemotherapy, radiotherapy or targeted therapy before surgery
2. History of other malignant tumors (excluding non-adenomatous colorectal neoplasms)
3. Pregnant or breastfeeding women
4. Severe concurrent systemic diseases that interfere with long-term follow-up or short-term survival (uncontrolled severe infection, organ failure, mental disorders, or other serious conditions)
5. Abnormal laboratory values or social/family factors judged by investigator to impede sample collection and follow-up
6. Simultaneous participation in other interventional clinical trials with mandatory assigned postoperative treatment regimen

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Driver-mutant Stage I-III Resectable Colon Adenocarcinoma Cohort; Patients pathologically diagnosed with stage I-III colon adenocarcinoma, curatively resected, carrying ≥1 oncogenic driver mutation (KRAS/NRAS/BRAF/PIK3CA), aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, without prior neoadjuvant therapy or other synchronous malignancy. All patients receive standard clinical surveillance plus serial blood draws for ctDNA-based MRD testing as observational biomarker testing only; no experimental treatment is assigned by the study protocol.

Other: Longitudinal ctDNA-MRD NGS testing at scheduled postoperative time points; biomarker test only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between postoperative ctDNA-MRD status and Recurrence-Free Survival (RFS)	RFS is defined as time from curative surgery to radiology/pathology-confirmed recurrence/metastasis, all-cause death, or last follow-up (whichever occurs first). Evaluate statistical association between MRD positive/negative status and RFS via survival analysis.	3 years post curative resection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between ctDNA-MRD status and Overall Survival (OS)	OS defined as time from enrollment to all-cause death; compare OS between MRD-positive and MRD-negative subgroups	3 years post curative resection
Median lead time of MRD positivity prior to radiologically confirmed tumor recurrence	Calculate average interval between first detectable ctDNA-MRD and CT-verified disease relapse to quantify early warning advantage of MRD surveillance	Up to 3 years postoperative follow-up
Association between dynamic ctDNA-MRD changes and adjuvant chemotherapy efficacy	Analyze clinical outcome across MRD trajectory subgroups: sustained negative, intermittent positive, sustained positive, seroconversion from negative to positive	3 years post curative resection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD positive detection rate stratified by distinct oncogenic driver mutation subtypes	Compare MRD detectability among driver gene mutant subgroups	All serial blood testing time points within 3-year follow-up
Prognostic predictive performance of ctDNA-MRD across different driver mutation subtypes	Evaluate heterogeneity of MRD's hazard ratio for recurrence among separate driver mutant cohorts	3 years post curative resection

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: The First Hospital of Jilin University

Publications and helpful links

General Publications

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
• Tie J, et al. Circulating tumor DNA dynamics predict recurrence and adjuvant chemotherapy benefit in colorectal cancer. N Engl J Med. 2020;382(6):545-555.
• Liu Y, et al. Genomic characteristics of resectable colorectal cancer and their impact on ctDNA MRD detection. Clin Cancer Res. 2025;31(12):2456-2467.
• BESPOKE Study Group. ctDNA MRD predicts recurrence and adjuvant chemotherapy benefit in stages II-III colorectal cancer. Lancet Oncol. 2025;26(5):689-701.
• Chinese Society of Pathology; Pathology Quality Control Center; Colorectal Cancer Expert Committee of Chinese Society of Clinical Oncology (CSCO). [Clinical practice guideline for molecular pathology in colorectal cancer (2025 version)]. Zhonghua Bing Li Xue Za Zhi. 2025 May 8;54(5):448-462. doi: 10.3760/cma.j.cn112151-20241206-00827. Chinese.

Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: August 23, 2026
• First Submitted That Met QC Criteria: August 26, 2026
• First Posted (Actual): August 31, 2026

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: PIK3CA; ctDNA; Colorectal Neoplasms; KRAS; Circulating Tumor DNA; BRAF; Multicenter Study; MRD; Prognostic Biomarker; Recurrence-Free Survival; Prospective Cohort; Molecular Residual Disease; Driver Mutation; Postoperative Surveillance
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Neuromuscular Diseases; Genetic Diseases, Inborn; Intestinal Diseases; Peripheral Nervous System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neurodegenerative Diseases; Colonic Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Colorectal Neoplasms; Colonic Neoplasms; Hereditary Sensory and Autonomic Neuropathies
• Other Study ID Numbers: ADX-DRIVER-CRC-V1.0-20260518

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Access Criteria: Requestors must provide a methodologically sound research proposal, and data access will be granted via secure de-identified dataset transfer after signed data use agreement. Supporting documents including full protocol, statistical analysis plan, informed consent template, and de-identified clinical dataset will be accessible for qualified researchers for secondary biomarker validation analyses. No identifying personal information will be shared under any circumstance.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No