A groundbreaking international clinical trial has revealed a transformative approach to determining which patients with stage 3 colon cancer truly require chemotherapy after surgery. This novel method employs a blood test that detects minuscule fragments of circulating tumour DNA (ctDNA) in the bloodstream, enabling a level of precision in treatment decisions that was previously unattainable. The trial, known as DYNAMIC-III, was spearheaded by Australia’s Walter and Eliza Hall Institute (WEHI) with collaboration from Johns Hopkins Kimmel Cancer Center and multiple international partners, fundamentally changing the standard paradigm for colorectal cancer care.
The DYNAMIC-III trial enrolled over 1,000 participants diagnosed with stage 3 colon cancer from Australia, New Zealand, and Canada. All patients underwent surgical resection aimed at removing the primary tumor. Approximately six weeks post-surgery, blood samples were collected for analysis of ctDNA, cancer-derived genetic fragments shed into the bloodstream through tumor cell apoptosis or necrosis. Detection of ctDNA after surgery acts as a highly sensitive biomarker for residual microscopic disease lurking beyond the reach of conventional imaging techniques.
Patients were stratified into two categories based on their ctDNA status: “low-risk” if no ctDNA was detectable, and “high-risk” if ctDNA fragments were present in circulation. This molecular categorization then guided randomized treatment allocations, comparing ctDNA-directed adjuvant chemotherapy regimens against standard chemotherapy protocols. The fundamental goal was to determine whether ctDNA testing could safely reduce overtreatment while maintaining cancer-free survival outcomes, representing a leap toward personalized medicine in colorectal oncology.
Professor Jeanne Tie from WEHI, a leading oncologist and the trial’s principal investigator, emphasizes that ctDNA-guided therapy embodies the future of precision oncology in this setting. While current guidelines advocate uniform administration of chemotherapy for all stage 3 colon cancer patients, often resulting in unnecessary exposure to cytotoxic drugs and associated toxicities, ctDNA assays can tailor treatment intensity based on molecular evidence of minimal residual disease (MRD). This nuanced approach ensures patients without detectable tumor DNA avoid the harsh side effects of chemotherapy like oxaliplatin-induced neuropathy without compromising survival chances.
The clinical data underscore the promise of this strategy. Patients categorized as ctDNA-negative post-surgery experienced remarkably favorable outcomes, with an impressive 87 percent remaining disease-free three years later. This suggests that a less aggressive chemo regimen or even omission of chemotherapy can be safe and effective in patients demonstrating molecular remission. Such precision spares patients from the physical and emotional burdens intrinsic to chemotherapy, substantially enhancing quality of life while preserving clinical efficacy.
Conversely, individuals with persistent ctDNA positivity faced a substantially elevated risk of recurrence. The study showed that only about half of these patients remained cancer-free at the three-year mark. Moreover, analysis revealed a dose-response relationship, where increasing ctDNA levels correlated with higher chances of tumor relapse. Importantly, intensification of chemotherapy in this subgroup did not improve outcomes, illuminating an urgent need for novel therapeutic strategies capable of targeting the biological pathways driving resistant or residual disease.
These findings were made possible through a seamless collaboration among several prominent organizations, including the Canadian Cancer Trials Group (CCTG), the Australasian Gastrointestinal Trials Group (AGITG), and the Peter MacCallum Cancer Centre. This multinational, multidisciplinary effort attests to the robustness and generalizability of the results, providing a strong impetus to integrate ctDNA testing into clinical oncology workflows globally.
Dr Jonathan Loree, Canadian senior investigator and DYNAMIC-III trial chair, highlights the study as the most compelling prospective evidence of ctDNA’s prognostic and predictive utility in resected stage 3 colon cancer to date. The trial’s rigorously designed randomized methodology addresses prior limitations in ctDNA research, establishing clinical validity that could fast-track incorporation into treatment guidelines. Dr Loree further stresses that these insights could also pave the way for refinements in other tumor types where MRD biomarkers hold promise.
Colorectal cancer remains a leading cause of cancer morbidity and mortality worldwide, with over 15,000 new diagnoses anticipated in Australia alone in 2024. This novel ctDNA-based liquid biopsy represents a paradigm shift, moving beyond traditional staging and histopathological factors to molecularly informed therapeutic decisions. Such advancements demonstrate how liquid biopsies, an emerging frontier in oncology, can revolutionize early detection of relapse, optimize adjuvant chemotherapy use, and ultimately improve patient survival.
The implications extend beyond clinical outcomes, promising a substantial reduction in healthcare costs and burden on patients’ lives by minimizing unnecessary treatments. By personalizing therapeutic interventions based on real-time molecular surveillance, DYNAMIC-III exemplifies how precision medicine is reshaping cancer care in the 21st century, reaffirming the critical role of translational research and international collaboration in advancing oncology.
In summary, the DYNAMIC-III trial decisively proves that ctDNA can serve as a sensitive, non-invasive biomarker to guide adjuvant chemotherapy in stage 3 colon cancer. This approach spares low-risk patients from unwarranted chemotherapy toxicity while identifying those at genuine high risk who require closer monitoring and potentially novel therapeutic approaches. As the oncology community embraces this innovation, patients stand to benefit from safer, more efficacious, and truly individualized treatment strategies that align with the molecular underpinnings of their disease.
Subject of Research: People
Article Title: Circulating Tumor DNA-Guided Adjuvant Therapy in Locally Advanced Colon Cancer: the Randomized Phase 2/3 DYNAMIC-III Trial
Web References:
10.1038/s41591-025-04030-w
Image Credits: WEHI
Keywords: Colon cancer, Cancer, Circulating tumor DNA, ctDNA, Adjuvant chemotherapy, Precision medicine, Minimal residual disease, Liquid biopsy
