Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial

Jeanne Tie^#^{1

2

3}, Yuxuan Wang^#⁴, Serigne N Lo^{5

6}, Kamel Lahouel^{7

8}, Joshua D Cohen⁴, Rachel Wong^{9

10}, Jeremy D Shapiro¹¹, Samuel J Harris¹², Adnan Khattak^{13

14}, Matthew E Burge¹⁵, Margaret Lee^{9

16}, Marion Harris¹⁷, Sue-Anne McLachlan¹⁸, Lisa Horvath¹⁹, Christos Karapetis²⁰, Jenny Shannon²¹, Madhu Singh²², Desmond Yip²³, Sumitra Ananda²⁴, Craig Underhill^{25

26}, Janine Ptak⁴, Natalie Silliman⁴, Lisa Dobbyn⁴, Maria Popoli⁴, Nickolas Papadopoulos⁴, Cristian Tomasetti^{7

8}, Kenneth W Kinzler⁴, Bert Vogelstein^#⁴, Peter Gibbs^#^{27

28

16}

Affiliations

¹ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
² Department of Medical Oncology, Peter MacCallum Cancer Centre, 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 Research and Biostatistics, Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
⁶ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁷ Center for Cancer Prevention, Early Detection and Monitoring, City of Hope, Duarte, CA, USA.
⁸ Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, AZ, USA.
⁹ Department of Medical Oncology, Eastern Health, 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, Cabrini Health, Melbourne, Victoria, Australia.
¹² Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia.
¹³ Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia.
¹⁴ Edith Cowan University, Perth, Western Australia, Australia.
¹⁵ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹⁶ Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.
¹⁷ Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia.
¹⁸ Department of Medical Oncology, St Vincent's Hospital, Melbourne, Victoria, Australia.
¹⁹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
²⁰ Department of Medical Oncology, Flinders Medical Centre, Adelaide, South Australia, Australia.
²¹ Department of Medical Oncology, Nepean Cancer Care Centre, Kingswood, New South Wales, Australia.
²² Department of Medical Oncology, Barwon Health, Geelong, Victoria, Australia.
²³ Department of Medical Oncology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
²⁴ Epworth Freemasons, Richmond, Melbourne, Victoria, Australia.
²⁵ Border Medical Oncology, Albury, New South Wales, Australia.
²⁶ Rural Medical School, Albury Campus, University of NSW, Albury, New South Wales, Australia.
²⁷ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
²⁸ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

^# Contributed equally.

PMID: 40055522
DOI: 10.1038/s41591-025-03579-w

Randomized Controlled Trial

Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial

Jeanne Tie et al. Nat Med. 2025 May.

. 2025 May;31(5):1509-1518.

doi: 10.1038/s41591-025-03579-w. Epub 2025 Mar 7.

Authors

Affiliations

¹ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. jeanne.tie@petermac.org.
² Department of Medical Oncology, Peter MacCallum Cancer Centre, 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 Research and Biostatistics, Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
⁶ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁷ Center for Cancer Prevention, Early Detection and Monitoring, City of Hope, Duarte, CA, USA.
⁸ Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, AZ, USA.
⁹ Department of Medical Oncology, Eastern Health, 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, Cabrini Health, Melbourne, Victoria, Australia.
¹² Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia.
¹³ Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia.
¹⁴ Edith Cowan University, Perth, Western Australia, Australia.
¹⁵ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹⁶ Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia.
¹⁷ Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia.
¹⁸ Department of Medical Oncology, St Vincent's Hospital, Melbourne, Victoria, Australia.
¹⁹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
²⁰ Department of Medical Oncology, Flinders Medical Centre, Adelaide, South Australia, Australia.
²¹ Department of Medical Oncology, Nepean Cancer Care Centre, Kingswood, New South Wales, Australia.
²² Department of Medical Oncology, Barwon Health, Geelong, Victoria, Australia.
²³ Department of Medical Oncology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
²⁴ Epworth Freemasons, Richmond, Melbourne, Victoria, Australia.
²⁵ Border Medical Oncology, Albury, New South Wales, Australia.
²⁶ Rural Medical School, Albury Campus, University of NSW, Albury, New South Wales, Australia.
²⁷ Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
²⁸ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

^# Contributed equally.

PMID: 40055522
DOI: 10.1038/s41591-025-03579-w

Abstract

Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval -5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; P = 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; P = 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (P < 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583 .

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Conflict of interest statement

Competing interests: J.T. 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 GSK. Y.W. is a consultant for Exact Sciences and Belay Diagnostics. B.V., K.W.K. and N.P. are founders of Thrive Earlier Detection, an Exact Sciences Company. K.W.K. and N.P. are consultants to Thrive Earlier Detection. B.V., K.W.K. and N.P. hold equity in Exact Sciences. N.P. is a consultant to Thrive Earlier Detection. B.V., K.W.K., J.D.C. and N.P. are founders of and own equity in Haystack Oncology and ManaT Bio. K.W.K. and N.P. are consultants to Neophore. K.W.K., B.V. and N.P. hold equity in and are consultants to CAGE Pharma. B.V. is a consultant to and holds equity in Catalio Capital Management. 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. and N.P. are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors and 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. Under a license agreement between Exact Sciences and the Johns Hopkins University, C.T. and the University are entitled to royalty distributions. C.T. has patent applications for intellectual property related to cancer early detection, is a member of the Scientific Advisory Board of PrognomiQ and an advisor for Haystack Oncology, and is also a paid consultant for the Rising Tide Foundation and Bayer AG. P.G. is a consultant to Haystack Oncology. The other authors declare no competing interests.

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Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial

Affiliations

Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous