Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer
Open accessAbstract
BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
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Because KRAS mutations are often clonal founder events, mutant KRAS ctDNA can serve as a highly informative molecular marker for tumor burden, treatment response, minimal residual disease, and emergence of resistance.
“Because KRAS mutations are often clonal founder events, mutant KRAS ctDNA can serve as a highly informative molecular marker for tumor burden, treatment response, minimal residual disease, and emergence of resistance [29,47,77,78].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [78]
The Abstract (Conclusions; page unavailable) describes ctDNA as evidence of minimal residual disease, and the Methods describe using postoperative ctDNA results to guide adjuvant treatment in stage II colon cancer. The cited paper does not establish that KRAS mutations are clonal founder events or that mutant KRAS ctDNA tracks tumor burden, treatment response, or emerging resistance. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFor EGFR TKIs, ctDNA increase preceded radiographic progression by a median of just under one month, though over 25% of patients had a lead time exceeding 3 months.
“This is in line with reported lead times of plasma progression versus radiographic progression, which showed the median lead time from ctDNA increase to radiographic progression was just under one month for EGFR TKIs, but greater than 25% of patients had a lead time of over 3 months.36”
From Early Changes in Circulating Cell-Free <i>KRAS</i> G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients (2023) · cites this paper as [36]
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Kano, Y. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135796
- Authors
- Tie, J., Cohen, J. D., Lahouel, K., Lo, S. N., Wang, Y., Kosmider, S., Wong, R., Shapiro, J., Lee, M., Harris, S., Khattak, A., Burge, M., Harris, M., Lynam, J., Nott, L., Day, F., Hayes, T., McLachlan, S.-A., Lee, B., Ptak, J., Silliman, N., Dobbyn, L., Popoli, M., Hruban, R., Lennon, A. M., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Tomasetti, C., & Gibbs, P.
- Affiliations
- The University of Sydney (AU)
- Edith Cowan University (AU)
- From the Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research (J.T., R.W., M.L., B.L., P.G.), the Department of Medical Oncology, Peter MacCallum Cancer Centre (J.T., B.L.), the Department of Medical Oncology, Western Health (J.T., S.K., M.L., P.G.), the Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne (J.T., P.G.), the Department of Medical Oncology, Eastern Health (R.W., M.L.), the Eastern Health Clinical School, Faculty of Medicine, Nursing, and Health Sciences, Monash University (R.W., M.L.), the Department of Medical Oncology, Cabrini Health (J.S.), the Department of Medical Oncology, Monash Health (M.H.), the Department of Medical Oncology, St. Vincent’s Hospital (S.-A.M.), and the Department of Medical Oncology, Northern Health (B.L.), Melbourne, VIC, the Research and Biostatistics Group, Melanoma Institute Australia, and the Faculty of Medicine and Health, University of Sydney, Sydney (S.N.L.), the Department of Medical Oncology, Bendigo...
- ORCID
- Tie, Jeanne
- Cohen, Joshua D.
- Lahouel, Kamel
- Lo, Serigne N.
- Wang, Yuxuan
- Kosmider, Suzanne
- Wong, Rachel
- Shapiro, Jeremy
- Lee, Margaret
- Harris, Sam
- Khattak, Adnan
- Burge, Matthew
- Harris, Marion
- Lynam, James
- Nott, Louise
- Day, Fiona
- Hayes, Theresa
- McLachlan, Sue-Anne
- Lee, Belinda
- Ptak, Janine
- Silliman, Natalie
- Dobbyn, Lisa
- Popoli, Maria
- Hruban, Ralph
- Lennon, Anne Marie
- Kinzler, Kenneth W.
- Vogelstein, Bert
- Tomasetti, Cristian
- Gibbs, Peter
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2022-06-16
- Volume
- 386
- Issue
- 24
- Pages
- 2261-2272
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC9701133
- OpenAlex
- W4281738617
- Cited by
- 1,091
- References
- 31
- Citations by year
- 2026: 274 · 2025: 247 · 2024: 252 · 2023: 228 · 2022: 89 · 2021: 1
- FWCI
- 85.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edith Cowan University Research Online (Edith Cowan University) (submittedVersion)
- Funders
- Victorian Cancer Agency (Clinical Research Fellowship 14007)
- John Templeton Foundation
- National Health and Medical Research Council (APP1085531, APP1194970)
- Eastern Health Foundation (Linda Williams Memorial Grant)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- circulating tumor DNA, stage II colon cancer, adjuvant chemotherapy, recurrence-free survival, oxaliplatin, fluoropyrimidine, non-inferiority, postoperative recurrence risk
- MeSH terms
- Circulating Tumor DNA, Oxaliplatin, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Australia, Colonic Neoplasms, Fluorouracil, Humans, Neoplasm Recurrence, Local, Neoplasm Staging, Chemotherapy, Adjuvant, Disease-Free Survival
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