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<p>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%; <i>P</i> &lt; 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; <i>P</i> &lt; 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.</p><p>Australian New Zealand Clinical Trials Registry Identifier: <a href="https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373948">ACTRN12617001566325</a>.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月20日

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  • Jeanne Tie,
  • Yuxuan Wang,
  • Jonathan M. Loree,
  • Joshua D. Cohen,
  • Rachel Wong,
  • Timothy Price,
  • Niall C. Tebbutt,
  • Val Gebski,
  • David Espinoza,
  • Matthew Burge,
  • Sam Harris,
  • James Lynam,
  • Belinda Lee,
  • Margaret M. Lee,
  • Daniel Breadner,
  • Marlyse Debrincat,
  • Siavash Foroughi,
  • Lorraine Chantrill,
  • Stephanie H. Lim,
  • Sharlene Gill,
  • Chris O’Callaghan,
  • Janine Ptak,
  • Natalie Silliman,
  • Lisa Dobbyn,
  • Maria Popoli,
  • Chetan Bettegowda,
  • Nicholas Papadopoulos,
  • Kenneth W. Kinzler,
  • Bert Vogelstein,
  • Peter Gibbs,
  • 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

摘要

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.