Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial.

2025-10-20

Tie, Jeanne

Wang, Yuxuan

Loree, Jonathan M

Cohen, Joshua D

Wong, Rachel

Price, Timothy

Tebbutt, Niall C

Gebski, Val

Espinoza, David

Burge, Matthew

Harris, Sam

Lynam, James

Lee, Belinda

Lee, Margaret M

Breadner, Daniel

Debrincat, Marlyse

Foroughi, Siavash

Chantrill, Lorraine

Lim, Stephanie H

Gill, Sharlene

O'Callaghan, Chris

Ptak, Janine

Silliman, Natalie

Dobbyn, Lisa

Popoli, Maria

Bettegowda, Chetan

Papadopoulos, Nicholas

Kinzler, Kenneth W

Vogelstein, Bert

Gibbs, Peter

Karanth , Narayan (Collaborator)

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.

Canadian Cancer Trials Group, Kingston, Ontario, Canada.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia.

Epworth Eastern, Epworth Healthcare, Melbourne, Victoria, Australia.

Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.

Department of Medical Oncology, The Queen Elizabeth and University of Adelaide, Adelaide, South Australia, Australia.

Warringal Private Hospital, Melbourne, Victoria, Australia.

NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.

NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.

Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

University of Queensland, Brisbane, Queensland, Australia.

Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia.

Newcastle Private Hospital, Newcastle, New South Wales, Australia.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia.

Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia.

Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.

Verspeeten Family Cancer Centre at the Schulich School of Medicine and Dentistry, London, Ontario, Canada.

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Department of Medical Oncology, Wollongong Hospital, Wollongong, New South Wales, Australia.

Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales, Australia.

Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.

Canadian Cancer Trials Group, Kingston, Ontario, Canada.

Canadian Cancer Trials Group, Kingston, Ontario, Canada.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Howard Hughes Medical Institute, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Howard Hughes Medical Institute, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Howard Hughes Medical Institute, Baltimore, MD, USA.

Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.

Journal Article

Publication

0000-0001-9244-2057

0000-0001-8189-2132

0000-0002-4926-5689

0000-0002-6742-820X

0000-0002-0947-9834

0000-0001-6916-8424

0000-0002-5790-0208

0000-0003-3306-3617

0000-0001-9991-7123

0000-0001-7135-7451

0000-0001-5591-1176

0000-0003-0766-3854

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .

link

Nat Med . 2025 Oct 20. doi: 10.1038/s41591-025-04030-w. Online ahead of print.

1546-170X

1546-170X

https://pubmed.ncbi.nlm.nih.gov/41115959/?otool=iaurydwlib