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Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer
Open accessAbstract
Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures: Detection of ctDNA and recurrence-free interval (RFI). Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.
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“There is a growing body of data demonstrating numerous clinical applications for ctDNA in adults with solid tumors, ranging from prognostication and evaluation of minimal residual disease (MRD) to detection of targetable alterations.7–12”
From Clinical Liquid Biopsy Testing for Detection of Actionable Genomic Alterations in Children and Young Adults With Advanced Solid Tumors on the GAIN Study (2026) · cites this paper as [11]
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“A salient example of the well-established relationship between ctDNA burden and disease status in adult solid tumors is the use of ctDNA for MRD detection and monitoring for recurrence in colorectal cancers.10–12”
From Clinical Liquid Biopsy Testing for Detection of Actionable Genomic Alterations in Children and Young Adults With Advanced Solid Tumors on the GAIN Study (2026) · cites this paper as [11]
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Self-citationMolecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer
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Metadata
- Authors
- Tie, J., Cohen, J. D., Wang, Y., Christie, M., Simons, K., Lee, M., Wong, R., Kosmider, S., Ananda, S., McKendrick, J., Lee, B., Cho, J. H., Faragher, I., Jones, I. T., Ptak, J., Schaeffer, M. J., Silliman, N., Dobbyn, L., Li, L., Tomasetti, C., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., & Gibbs, P.
- Affiliations
- The University of Melbourne (AU)
- Johns Hopkins University (US)
- The Royal Melbourne Hospital (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Western Health (AU)
- Eastern Health (AU)
- Division of Biostatistics & Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Corresponding author
- Tie, Jeanne
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-12-01
- Volume
- 5
- Issue
- 12
- Pages
- 1710
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6802034
- OpenAlex
- W2980567593
- Cited by
- 668
- References
- 28
- Citations by year
- 2026: 76 · 2025: 91 · 2024: 104 · 2023: 124 · 2022: 107 · 2021: 102 · 2020: 57 · 2019: 6
- FWCI
- 21.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA062924)
- National Institute of General Medical Sciences (T32GM136577)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- circulating tumor DNA, stage III colon cancer, adjuvant chemotherapy, recurrence risk, minimal residual disease, recurrence-free interval, somatic mutations, liquid biopsy, predictive biomarkers, treatment response monitoring, recurrent colorectal cancer, recurrence-free survival, prognostic factors
- MeSH terms
- Circulating Tumor DNA, Adult, Aged, Aged, 80 and over, Australia, Colonic Neoplasms, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Risk Factors, Biomarkers, Tumor, Treatment Outcome, Chemotherapy, Adjuvant, Neoplasm, Residual, Disease-Free Survival, Precision Medicine, High-Throughput Nucleotide Sequencing
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