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

Jeanne Tie^#^{1

2

3}, Yuxuan Wang^#^{4

5}, Jonathan M Loree^{6

7}, Joshua D Cohen^{4

5}, Rachel Wong^{8

9

10}, Timothy Price¹¹, Niall C Tebbutt¹², Val Gebski¹³, David Espinoza¹³, Matthew Burge^{14

15}, Sam Harris¹⁶, James Lynam¹⁷, Belinda Lee^{18

19

20}, Margaret M Lee^{8

21}, Daniel Breadner²², Marlyse Debrincat^{19

23}, Siavash Foroughi^{19

23}, Lorraine Chantrill²⁴, Stephanie H Lim²⁵, Sharlene Gill^{6

7}, Chris O'Callaghan⁷, Janine Ptak^{4

5

26}, Natalie Silliman^{4

5

26}, Lisa Dobbyn^{4

5}, Maria Popoli^{4

5}, Chetan Bettegowda^{4

5

27}, Nicholas Papadopoulos^{4

5

28}, Kenneth W Kinzler^{4

5

28}, Bert Vogelstein^#^{4

5

26

28}, Peter Gibbs^#^{19

23

21}; AGITG DYNAMIC-III Study Group (Intergroup Study of the Australasian Gastro-Intestinal Trials Group and Canadian Cancer Trials Group)

Collaborators, Affiliations

Collaborators

AGITG DYNAMIC-III Study Group (Intergroup Study of the Australasian Gastro-Intestinal Trials Group and Canadian Cancer Trials Group):
Sue-Anne McLachlan, Madhu Singh, Theresa Hayes, Joanne Lundy, Zee Wan Wong, Geoff Chong, Ayesha Saqib, Simone Steel, Morteza Aghmesheh, Stephen Begbie, Aflah Roohullah, Philip Beale, Weng Ng, Connie Diakos, Ratnesh Srivastav, Sunil Rai, Matt Wong, Deme Karikios, Megan Barnett, Caroline Lum, Craig Underhill, Pirooz Poursoltan, Bhaskar Karki, Chris Karapetis, Tim Price, Adnan Khattak, Melanie Wuttke, Narayan Karanth, Mark Jeffery, Radhika Yelamanchili, Anupam Batra, Daryl Roitman, Joanna Gotfrit, Iqbal Mussawar, Shaqil Kassam, John Goffin, Sara Rask, Stacey Hubay, Eric Chen, Setareh Samimi, Samuel Martel, Urszula Zurawska, Ralph Wong, Lucas Sideris, Patricia Tang, John McGhie, Saroosh Arif, Shahid Ahmed, James Michael, Katharine Shim, Sam Babak, Dawn Armstrong, Ron Burkes, Petr Kavan

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
² Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
³ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
⁴ Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
⁷ Canadian Cancer Trials Group, Kingston, Ontario, Canada.
⁸ Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia.
⁹ Epworth Eastern, Epworth Healthcare, Melbourne, Victoria, Australia.
¹⁰ Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
¹¹ Department of Medical Oncology, The Queen Elizabeth and University of Adelaide, Adelaide, South Australia, Australia.
¹² Warringal Private Hospital, Melbourne, Victoria, Australia.
¹³ NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹⁵ University of Queensland, Brisbane, Queensland, Australia.
¹⁶ Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia.
¹⁷ Newcastle Private Hospital, Newcastle, New South Wales, Australia.
¹⁸ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁹ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
²⁰ Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia.
²¹ Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.
²² Verspeeten Family Cancer Centre at the Schulich School of Medicine and Dentistry, London, Ontario, Canada.
²³ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.
²⁴ Department of Medical Oncology, Wollongong Hospital, Wollongong, New South Wales, Australia.
²⁵ Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales, Australia.
²⁶ Howard Hughes Medical Institute, Baltimore, MD, USA.
²⁷ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

^# Contributed equally.

PMID: 41115959
DOI: 10.1038/s41591-025-04030-w

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

Jeanne Tie et al. Nat Med. 2025.

. 2025 Oct 20.

doi: 10.1038/s41591-025-04030-w. Online ahead of print.

Authors

Collaborators

AGITG DYNAMIC-III Study Group (Intergroup Study of the Australasian Gastro-Intestinal Trials Group and Canadian Cancer Trials Group):
Sue-Anne McLachlan, Madhu Singh, Theresa Hayes, Joanne Lundy, Zee Wan Wong, Geoff Chong, Ayesha Saqib, Simone Steel, Morteza Aghmesheh, Stephen Begbie, Aflah Roohullah, Philip Beale, Weng Ng, Connie Diakos, Ratnesh Srivastav, Sunil Rai, Matt Wong, Deme Karikios, Megan Barnett, Caroline Lum, Craig Underhill, Pirooz Poursoltan, Bhaskar Karki, Chris Karapetis, Tim Price, Adnan Khattak, Melanie Wuttke, Narayan Karanth, Mark Jeffery, Radhika Yelamanchili, Anupam Batra, Daryl Roitman, Joanna Gotfrit, Iqbal Mussawar, Shaqil Kassam, John Goffin, Sara Rask, Stacey Hubay, Eric Chen, Setareh Samimi, Samuel Martel, Urszula Zurawska, Ralph Wong, Lucas Sideris, Patricia Tang, John McGhie, Saroosh Arif, Shahid Ahmed, James Michael, Katharine Shim, Sam Babak, Dawn Armstrong, Ron Burkes, Petr Kavan

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
² Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
³ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
⁴ Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
⁷ Canadian Cancer Trials Group, Kingston, Ontario, Canada.
⁸ Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia.
⁹ Epworth Eastern, Epworth Healthcare, Melbourne, Victoria, Australia.
¹⁰ Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
¹¹ Department of Medical Oncology, The Queen Elizabeth and University of Adelaide, Adelaide, South Australia, Australia.
¹² Warringal Private Hospital, Melbourne, Victoria, Australia.
¹³ NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹⁵ University of Queensland, Brisbane, Queensland, Australia.
¹⁶ Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia.
¹⁷ Newcastle Private Hospital, Newcastle, New South Wales, Australia.
¹⁸ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁹ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
²⁰ Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia.
²¹ Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.
²² Verspeeten Family Cancer Centre at the Schulich School of Medicine and Dentistry, London, Ontario, Canada.
²³ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.
²⁴ Department of Medical Oncology, Wollongong Hospital, Wollongong, New South Wales, Australia.
²⁵ Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales, Australia.
²⁶ Howard Hughes Medical Institute, Baltimore, MD, USA.
²⁷ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

^# Contributed equally.

PMID: 41115959
DOI: 10.1038/s41591-025-04030-w

Abstract

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 .

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Conflict of interest statement

Competing interests: J.T. has served as an advisor/consultant for Haystack Oncology, Amgen, Novartis, AstraZeneca, Merck Serono, Merck Sharp & Dohme, BeiGene, Pierre Fabre, Bristol Myers Squibb, Gilead, Roche, Takeda and Daiichi-Sankyo and reports funding to their institution from Pfizer, Roche, Grail, Pierre Fabre, Daiichi-Sankyo, Zentalis, AstraZeneca and GlaxoSmithKline. Y.W. is a consultant to Belay Diagnostics and Haystack Oncology. J.L. consults for Taiho, Ipsen, Pfizer, Amgen, Merck, GlaxoSmithKline and Novartis and received research funding from Ipsen, Amgen, AstraZeneca, Foundation Medicine, Bayer, Personalis Inc., Guardant and Agenus. B.V. and K.W.K. are founders of Exact Sciences. K.W.K. and N.P. are advisors to, and hold equity in, Exact Sciences. B.V., K.W.K. and N.P. are founders of, and hold equity in, Clasp Therapeutics and Haystack Oncology, a Quest Diagnostics company. K.W.K., B.V. and N.P. are consultants to, and hold equity in, CAGE Pharma. B.V. is a consultant to, and holds equity in, Catalio Capital Management. C.B. is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology and Galectin Therapeutics. C.B. is also a co-founder of OrisDx and a co-founder of Belay Diagnostics. M.P. is a consultant to Haystack Oncology. L.D. is an employee of Haystack Oncology. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. B.V., K.W.K., N.P. and C.B. are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Patent applications on the work described in this paper may be filed by Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. D.B. has received honoraria for consultancies from AstraZeneca, Janssen, BeiGene, Boehringer Ingelheim, Bayer, Guardant Health and Amgen and speaking fees from Merck, AstraZeneca and Roche. P.G. is a consultant to Haystack Oncology. The remaining authors declare no competing interests.

References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources