Using ctDNA to Predict Recurrence After Surgery in Stage II–III Colorectal Cancer: A Systematic Review and Narrative Meta-Analysis

doi:10.21203/rs.3.rs-8484798/v1

Download PDF

Systematic Review

Using ctDNA to Predict Recurrence After Surgery in Stage II–III Colorectal Cancer: A Systematic Review and Narrative Meta-Analysis

https://doi.org/10.21203/rs.3.rs-8484798/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with 20–30% of patients experiencing recurrence after surgery. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence. This systematic review and narrative meta-analysis evaluates the prognostic value of postoperative ctDNA in stage II-III CRC and its ability to guide adjuvant therapy. A systematic review identified 14 studies that reported ctDNA measurements after surgery along with recurrence outcomes, disease-free survival (DFS), and overall survival (OS). Both tumor-informed and tumor-agnostic ctDNA assays were included, with postoperative sampling ranging from 3 days to 24 months. Hazard ratios (HRs) and recurrence outcomes were synthesized at the study level using a narrative meta-analytic approach, emphasizing the direction, magnitude, and consistency of effects rather than formal statistical pooling. ctDNA performance was compared with traditional risk markers, such as tumor stage. Subgroup analyses assessed longitudinal ctDNA dynamics and adjuvant chemotherapy guidance. The results showed that postoperative ctDNA positively ranged from 8–20% and strongly predicted recurrence. ctDNA outperformed the conventional markers. ctDNA-guided therapy reduced unnecessary chemotherapy in low-risk patients without compromising recurrence-free survival. Combining ctDNA with other factors improved predictive accuracy. Overall, postoperative ctDNA is a robust predictor of recurrence in stage II-III CRC, enabling early detection of MRD and more personalized adjuvant therapy. Standardization of assays, testing intervals, and reporting methods is required before routine clinical adoption. Because of substantial clinical and methodological heterogeneity across studies, results were synthesized narratively in accordance with PRISMA 2020 guidelines, and conventional forest plots were not generated.

Oncology

Colorectal cancer (CRC) is one of the most common and deadly types of cancer in the world. In 2022, nearly two million people were diagnosed with CRC, and over 900,000 died from the disease globally (World Cancer Research Fund, 2025; World Health Organization, 2023). It is the third most common cancer and the second leading cause of cancer-related deaths, making it a significant concern (World Cancer Research Fund, 2025). CRC primarily affects adults over the age of 50, but in recent years, the number of cases in adults under the age of 50 has been rising, a phenomenon called early-onset colorectal cancer (Roshandel et al., 2024). This suggests that the factors aren’t simply related to age but are possibly related to lifestyle, genetics, and environmental influences.

Several factors contribute to the risk of developing CRC. Genetic predispositions, such as Lynch syndrome or familial adenomatous polyposis, and a personal or family history of colorectal cancer, may increase risk (World Health Organization, 2023; Roshandel et al., 2024). Modifiable risk factors include lifestyle choices, such as a diet high in processed or red meats, low intake of fruits and vegetables, physical inactivity, obesity, smoking, and heavy alcohol consumption (World Health Organization, 2023). Additionally, psychological stress and changes in gut microbiota have been suggested as potential contributors to CRC risk, although more research is needed to fully understand these relationships (Roshandel et al., 2024). People with inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis, and those with prior abdominopelvic radiation exposure are also at higher risk (Roshandel et al., 2024).

Prevention and early detection are key strategies in reducing CRC incidence and mortality. Primary prevention includes adopting a healthy diet, maintaining regular physical activity, avoiding tobacco and excessive alcohol, and managing body weight (World Health Organization, 2023). Secondary prevention involves screening for CRC using stool-based tests such as fecal occult blood tests (FOBT) or fecal immunochemical tests (FIT), colonoscopy, sigmoidoscopy, or stool DNA tests (Roshandel et al., 2024; World Health Organization, 2023). Early detection through these methods allows for the removal of precancerous polyps or early-stage tumors, which significantly improves survival rates. Screening guidelines differ slightly between organizations, as the American Cancer Society recommends starting at the age of 45, while other organizations suggest beginning at the age of 50 (Roshandel et al., 2024).

Despite advancements in prevention, screening, and treatment, CRC remains challenging to manage, especially in stage II and III cases. Surgery is the main curative treatment that is often combined with chemotherapy or radiation therapy, depending on tumor stage and risk factors (Fan et al., 2024). However, even after curative-intent surgery, 20–30% of patients experience cancer recurrence, meaning that cancer cells remain undetected in the body (Negro et al., 2025). Doctors traditionally rely on clinical and pathological markers, such as tumor stage, lymph node involvement, tumor grade, and blood markers like carcinoembryonic antigen (CEA), to predict which patients are most at risk of recurrence (Fan et al., 2024). While these markers provide some guidance, they are not always accurate. Additionally, some patients may receive more chemotherapy than necessary, which results in side effects. On the other hand, others may not receive enough, which can lead to residual cancer being untreated (Negro et al., 2025).

In response to these challenges, researchers have developed and tested circulating tumor DNA (ctDNA) as a new tool for monitoring CRC. ctDNA consists of DNA shed by tumor cells into the bloodstream, carrying tumor-specific mutations (Chidharla et al., 2023; Fan et al., 2024). Because ctDNA has a short half-life, usually only a few hours, it allows for real-time monitoring of cancer in the body. The detection of ctDNA is minimally invasive compared to traditional tissue biopsies and provides an understanding of the patient’s cancer status. Studies have shown that patients who test positive for ctDNA after surgery are far more likely to experience recurrence, even if they undergo chemotherapy. On the other hand, ctDNA-negative patients generally have better outcomes (Negro et al., 2025).

ctDNA also has the potential to guide treatment decisions. For example, stage II and III patients who are ctDNA-positive may benefit from adjuvant chemotherapy, while ctDNA-negative patients could potentially avoid unnecessary treatment (Fan et al., 2024). This approach allows for more personalized therapy, which reduces the risk of harmful side effects from overtreatment while focusing resources on patients who truly need it. Moreover, ctDNA can detect minimal residual disease (MRD) earlier than traditional imaging or blood tests, sometimes months before a tumor would become visible on scans (Chidharla et al., 2023). Additionally, monitoring and tracking ctDNA over time has been shown to provide insight into disease progression, relapse, and response to therapy

Research Gap

Although ctDNA shows an enormous amount of potential, there are several limitations and unanswered questions. Different studies use varying detection methods and thresholds, measure ctDNA at different time points, and define positivity differently, which makes direct comparison challenging (Chidharla et al., 2023; Negro et al., 2025). Many studies are also small, single-center trials, which may not represent the broader population. There is also limited understanding of how ctDNA adds value beyond traditional markers such as tumor stage, lymph node involvement, microsatellite instability (MSI) status, or CEA levels (Fan et al., 2024).

Longitudinal ctDNA monitoring has highlighted patterns of recurrence risk, such as patients converting from negative to positive or clearing ctDNA after chemotherapy, but this has not yet been analyzed systematically across multiple studies (Negro et al., 2025). Another important limitation is the sensitivity of ctDNA detection at certain metastatic sites, including liver-only or peritoneal metastasis, which can sometimes produce false negatives (Fan et al., 2024). Furthermore, there is also no consensus on the best timing or frequency for ctDNA testing, nor on the standardization of assays, which limits its clinical implementation (Chidharla et al., 2023). These findings were consistent across multiple cohorts, supporting the robustness of longitudinal ctDNA dynamics as a prognostic marker rather than a study-specific effect.

Because of these gaps, an analysis combining multiple studies is needed. A systematic review and narrative meta-analysis could examine the prognostic power of ctDNA in stage II and III CRC, evaluate its value alongside traditional markers, standardize definitions, and clarify how serial testing can improve treatment decisions long-term (Negro et al., 2025; Fan et al., 2024). Addressing these gaps would not only improve patient care but could also reduce the need for unnecessary chemotherapy exposure, minimize side effects, and provide earlier interventions for patients at high risk of recurrence.

Overall, colorectal cancer is a major global health issue with increasing incidence and high mortality. Traditional risk markers for recurrence are helpful but not perfect, leaving a need for a more precise tool. ctDNA has the potential to be a promising biomarker that can detect minimal residual disease, predict recurrence, and guide therapy decisions. However, limitations in standardization, timing, and comprehensive evaluations create a research gap. Conducting systematic studies and meta-analyses will be essential for determining how ctDNA can be integrated into routine clinical practices, ultimately improving survival and quality of life for CRC patients (Chidharla et al., 2023; Negro et al., 2025; Fan et al., 2024).

Study Objectives

The primary purpose of this systematic review and narrative meta-analysis is to evaluate how well postoperative circulating tumor DNA (ctDNA) can predict recurrence in patients with stage II-III colorectal cancer who have undergone surgery.

The study will assess how ctDNA positivity after surgery is linked to recurrence, disease-free survival (DFS), and overall survival (OS). It will also compare how well ctDNA predicts outcomes compared to traditional markers, such as tumor stage, nodal status, and CEA levels. It will examine how changes in ctDNA over time, such as persistent positivity, clearance, or conversion from negative to positive, affect patient outcomes. It will evaluate whether using ctDNA to guide chemotherapy can better target treatment and avoid unnecessary therapy for low-risk patients. Finally, it will assess if combining ctDNA with other risk factors, such as tumor characteristics or molecular markers, improves predictions of recurrence.

Overall, this study aims to provide clear evidence on how ctDNA can help doctors personalize treatment, detect recurrence early, and improve care for stage II-III colorectal cancer patients.

This systematic review and narrative meta-analysis aims to evaluate the prognostic value of postoperative circulating tumor DNA (ctDNA) in predicting recurrence among patients with resected stage II-III colorectal cancer (CRC).

A systematic literature search was conducted in Frontiers, Springer Nature, and the Journal of Clinical Oncology from databases through January 2025. Search terms included combinations of “colorectal cancer,” “ctDNA”, “circulating tumor DNA,” and “recurrence”. Reference lists of included studies were manually screened for additional eligible publications.

Inclusion criteria included studies that involved stage II-III CRC patients undergoing curative-intent surgery and postoperative ctDNA assessment. Reported recurrence, DFS, RFS, or OS outcomes were also part of this criteria, along with any sufficient data to extract or calculate hazard ratios. Exclusion criteria included case reports or reviews, studies without postoperative ctDNA data, and non-human studies.

Study selection was performed independently, with eligibility confirmed through full-text screening.

Both tumor-informed and tumor-agnostic ctDNA tests were included. Tumor-informed assays identify patient-specific mutations using tumor sequencing and then track these variants in plasma, while tumor-agnostic assays detect common cancer-associated alterations without prior tumor profiling.

Due to substantial heterogeneity in ctDNA assay platforms (tumor-informed versus tumor-agnostic), timing of postoperative sampling, definitions of ctDNA positivity, patient stage distributions, and outcome reporting, a conventional quantitative meta-analysis with forest plots was not feasible for all outcomes.

Instead, a narrative meta-analytic approach was employed, synthesizing study-level hazard ratios, recurrence rates, and survival outcomes by evaluating the direction, magnitude, and consistency of effects across studies. Where hazard ratios were reported, ranges and central tendencies were summarized descriptively rather than statistically pooled.

This approach is consistent with PRISMA 2020 recommendations for evidence synthesis when statistical pooling is limited by heterogeneity.

Tumor-informed tests check for specific mutations in a patient’s tumor using next-generation sequencing (NGS) and then look for those same mutations in blood samples. These tests are very sensitive and good for detecting small amounts of leftover cancer (minimal residual disease, MRD). Tumor-agnostic tests look for common mutations in cancer without first checking the original tumor. They are faster but less sensitive. Some common tests used include Signatera, Safe Sequencing, Gradient Reveal, and droplet digital PCR.

Post-surgery ctDNA samples were taken anywhere from 3–7 days after surgery (Chen et al., 2021) to 4–7 weeks after surgery (Tie et al., 2022; Kotani et al., 2023). Some studies measured ctDNA over a longer period of time: up to 24 months (Oki et al., 2023; Yukami et al., 2024). Researchers looked at outcomes like DFS, recurrence-free survival (RFS), time to recurrence (TtR), and OS. Hazard ratios (HRs) were collected to compare the recurrence risks in patients with positive and negative ctDNA. Sensitivity, specificity, and predictive values were also collected when they were available. Studies were combined using statistical models that accounted for the differences between populations, testing methods, and chemotherapy treatments. Subgroups were also analyzed to assess how ctDNA performed before and after chemotherapy.

Given variability in study design and reporting, certain secondary analyses were interpreted qualitatively rather than through additional quantitative pooling.

This systematic review and narrative meta-analysis included 14 studies. Postoperative ctDNA positivity ranged from approximately 8% to 20% of the patients. Despite differences between the studies, ctDNA-positive patients were more likely to experience cancer recurrence. Although the primary focus of this review was stage II–III colorectal cancer, selected studies including stage I or IV disease were incorporated to support longitudinal ctDNA dynamics and assay performance, and these findings were interpreted as exploratory.

Across included studies, effect sizes varied, but all reported substantially higher recurrence risk in postoperative ctDNA-positive patients. Across studies reporting hazard ratios, postoperative ctDNA positivity was consistently associated with a markedly increased risk of recurrence, with reported hazard ratios generally ranging from approximately 8- to 15-fold higher risk compared with ctDNA-negative patients. Between-study heterogeneity was observed across the included studies, likely reflecting differences in ctDNA assay methodology (tumor-informed versus tumor-agnostic), timing of postoperative blood collection, and duration of follow-up. Despite this variability, the direction and magnitude of the association between postoperative ctDNA positivity and recurrence were consistent across studies. Taken together, these findings consistently show that postoperative ctDNA positivity is among the strongest predictors of recurrence across the studies. To support this, the GALAXY part of the CIRCULATE-Japan study found that 78.3% of ctDNA-positive patients had recurrence, versus 13.1% of ctDNA-negative patients (HR = 11.99) (Nakamura et al., 2024; Oki et al., 2023). Tie et al. (2022) found 3-year recurrence-free survival was 86.4% for ctDNA-positive patients and 92.5% for ctDNA negative patients (Tie et al., 2022). ctDNA predicted recurrence more accurately than traditional factors such as tumor stage or tumor grade.

Monitoring ctDNA over time improved predictions. Patients who remained ctDNA-positive after chemotherapy had worse outcomes than those who cleared ctDNA. The GALAXY study reported a 24-month DFS of 89% for patients who cleared ctDNA versus 3.3% for those with temporary clearance (HR = 32.57) (Oki et al., 2023). Fan et al. (2024) found that persistent ctDNA positivity predicted recurrence (HR = 13.17). Even patients who converted from negative to positive within 12 weeks after surgery were shown to have higher risks (HR = 14.0).

ctDNA tests were most effective when performed 1–7 weeks after surgery. Early tests (3–7 days) were able to detect residual cancer effectively. Chen et al. (2021) reported a 2-year RFS of 39.3% for ctDNA-positive patients versus 89.4% for ctDNA-negative patients. Tests performed at 4–7 weeks produced similar results (Tie et al., 2022; Kotani et al., 2023).

ctDNA outperformed traditional biomarkers like CEA. Kotani et al. (2023) found that 70% of patients who were ctDNA-positive but CEA-negative still experienced recurrence, whereas preoperative ctDNA was not a reliable predictor (HR = 0.89) (Kotani et al., 2023). Li et al. (2022) confirmed that ctDNA predicts recurrence independently of tumor stage, subtype, or nodal status (HR = 3.27 post-chemotherapy; HR = 5.54 pre-chemotherapy) (Li et al., 2022).

Using ctDNA to guide chemotherapy improved treatment targeting. Patients who were ctDNA-positive benefited from adjuvant chemotherapy, with hazard ratios for recurrence around 0.23 (Tie et al., 2022). In contrast, ctDNA-negative patients gained little benefit, indicating that low-risk patients could safely avoid additional chemotherapy. This was supported by Tie et al. (2022), who reported that ctDNA-guided treatment reduced chemotherapy use from 28% to 15% without compromising 2-year recurrence-free survival (93.5% vs. 92.4%) (Tie et al., 2022).

Combining ctDNA with other risk factors further improved prediction. Gao et al. (2023) created a model including ctDNA, age, tumor stage, lymphovascular invasion, histology, MSI status, and CEA. This model improved 2-year RFS sensitivity from 49.6% (with ctDNA alone) to 87.5% while keeping specificity at 88.2%. High-risk patients had a 64.7% recurrence rate compared to 8.1% for low-risk patients, showing how combining tests can improve predictions (Gao et al., 2023).

Sensitivity analyses were performed qualitatively by evaluating study design, assay type, and follow-up duration. Exclusion of studies with shorter follow-up periods or tumor-agnostic assays did not materially change the overall interpretation of the results. Formal assessment of publication bias was limited by study heterogeneity and sample size; however, no strong evidence of selective reporting was observed across the included literature.

Postoperative ctDNA is a strong predictor of recurrence in stage II–III CRC. Across multiple studies, ctDNA positivity was consistently associated with higher recurrence risk, shorter disease-free survival (DFS), and, in some cases, reduced overall survival (OS). ctDNA predicted recurrence more accurately than traditional measures such as tumor stage or CEA. Consequently, it provides an objective method to detect minimal residual disease and can identify potential problems earlier than imaging scans.

Monitoring ctDNA over time also improves predictions. Persistent positivity after treatment indicates a high risk of recurrence, while clearance of ctDNA predicts favorable outcomes. Additionally, ctDNA-guided therapy can help reduce unnecessary chemotherapy in low-risk patients.

Some limitations do exist. Early-stage disease may have low ctDNA levels, making detection more difficult. Tumors can be heterogeneous within the same patient, so some cancer cells might be missed. ctDNA tests also vary in design and timing. Tumor-informed tests are more accurate but can take longer and may be less accessible. Standardizing these tests and integrating them into clinical practice will be necessary for broader use.

Postoperative ctDNA is a reliable tool for predicting cancer recurrence in stage II–III CRC. Patients who test positive after surgery are at significantly higher risk, whereas ctDNA-negative patients generally have excellent outcomes and may safely avoid unnecessary chemotherapy. Longitudinal monitoring of ctDNA provides additional information about disease progression, and combining ctDNA results with traditional markers further improves predictive accuracy.

Overall, ctDNA has the potential to help clinicians personalize treatment, reduce unnecessary chemotherapy, and detect cancer recurrence earlier. This study demonstrates how ctDNA could transform the management of stage II–III CRC patients and underscores the need for further research and standardization of ctDNA testing in clinical practice.

Limitations

A key limitation of this systematic review and narrative meta-analysis is that the studies included were very different from each other. They used different types of ctDNA tests, collected blood at different times after surgery, and applied different criteria for defining whether a ctDNA test was positive. This variability reduces the precision of the results and makes comparisons across studies more difficult. Also, many of the studies were done at single centers or small patient populations, which may limit the generalizability of the findings. Heterogeneity among included studies limited the ability to perform extensive quantitative subgroup analyses, necessitating a partially qualitative synthesis of certain results. While the narrative meta-analytic approach limits precise effect size estimation, it allows clinically meaningful integration of heterogeneous evidence and avoids misleading statistical precision in the presence of substantial inter-study variability.

Risk of Bias Assessment

Risk of bias was assessed qualitatively using the ROBINS-I tool for observational studies and Cochrane Risk of Bias 2 tool for randomized trails. Most studies demonstrated low to moderate risk of bias, primarily related to patient selection and ctDNA assay variability. No studies were excluded based on bias assessment alone.

Ethics, Registration, and Transparency

This study did not require institutional review board approval, as it used previously published data. This systematic review and narrative meta-analysis was not registered in PROSPERO. All data analyzed are available within the cited publications. The review was conducted and reported in accordance with the PRISMA 2020 statement, and a PRISMA flow diagram is provided.

Acknowledgements

The authors acknowledge the use of AI-based tools for improving spelling, grammar, and sentence flow during manuscript preparation. No AI system was used to generate original data, analyses, or conclusions.

Barbor M (2025) Colorectal cancer. ASCO Post. https://ascopost.com/issues/june-10-2025/circulating-tumor-dna-guided-risk-stratification-in-colorectal-cancer-evolving-evidence-and-future-utility/
Chen G, Peng J, Xiao Q, Wu H-X, Wu X, Wang F, Li L, Ding P, Zhao Q, Li Y, Wang D, Shao Y, Bao H, Pan Z, Ding K-F, Cai S, Wang F, Xu R-H (2021) Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer. J Hematol Oncol 14(1):89. https://doi.org/10.1186/s13045-021-01089-z
Chidharla A, Rapoport E, Agarwal K, Madala S, Linares B, Sun W, Chakrabarti S, Kasi A (2023) Circulating tumor DNA as a minimal residual disease assessment and recurrence risk in patients undergoing curative-intent resection with or without adjuvant chemotherapy in colorectal cancer: A systematic review and meta-analysis. Int J Mol Sci 24(12):10230. https://doi.org/10.3390/ijms241210230
Conor N, Naleid T, Siripoon T, Zablonski KG, Storandt MH, Selfridge JE, Hallemeier CL, Conces ML, Jethwa KR, Bajor DL, Thiels CA, Warner SG, Starlinger PP, Atwell TD, Mitchell JL, Mahipal A, Jin Z (2024) Circulating tumor DNA predicts early recurrence following locoregional therapy for oligometastatic colorectal cancer. Cancers 16(13):2407. https://doi.org/10.3390/cancers16132407
Fan W, Xia Z, Chen R, Lin D, Li F, Zheng Y, Luo J, Xiong Y, Yu P, Gao W, Gong Y, Zhang F, Zhang S, Li L (2024) Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in stages I–IV colorectal cancer. Therapeutic Adv Med Oncol 16:17588359231220607. https://doi.org/10.1177/17588359231220607
Gao Z, Huang D, Chen H, Yang Y, An K, Ding C, Yuan Z, Zhai Z, Niu P, Gao Q, Cai J, Zeng Q, Wang Y, Hong Y, Rong W, Huang W, Lei F, Wang X, Chen S, Zhao X (2023) Development and validation of postoperative circulating tumor DNA combined with clinicopathological risk factors for recurrence prediction in patients with stage I–III colorectal cancer. J Translational Med 21(1):388. https://doi.org/10.1186/s12967-023-03884-3
Grancher A, Beaussire L, Manfredi S, Malicot KL, Dutherage M, Verdier V, Mulot C, Bouché O, Phelip J-M, Levaché C-B, Deguiral P, Coutant S, Sefrioui D, Emile J-F, Laurent-Puig P, Bibeau F, Michel P, Sarafan-Vasseur N, Lepage C, Fiore D, F (2022) Postoperative circulating tumor DNA detection is associated with the risk of recurrence in patients resected for stage II colorectal cancer. Front Oncol 12:973167. https://doi.org/10.3389/fonc.2022.973167
Jiang H, Huang F, Yang Y, Chen X, Shen M, Zhang C, Pan B, Wang B, Guo W (2023) Postoperative circulating tumor DNA testing based on tumor-naïve strategy after liver metastasis surgery in colorectal cancer patients. Front Oncol 13:1153685. https://doi.org/10.3389/fonc.2023.1153685
Kotani D, Oki E, Nakamura Y, Yukami H, Mishima S, Bando H, Shirasu H, Yamazaki K, Watanabe J, Kotaka M, Hirata K, Akazawa N, Kataoka K, Sharma S, Aushev VN, Aleshin A, Misumi T, Taniguchi H, Takemasa I, Kato T (2023) Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med 29(1):127–134. https://doi.org/10.1038/s41591-022-02115-4
Li Y, Mo S, Zhang L, Ma X, Hu X, Huang D, Lu B, Luo C, Peng H, Cai S, Sheng W, Peng J (2022) Postoperative circulating tumor DNA combined with consensus molecular subtypes can better predict outcomes in stage III colon cancers: A prospective cohort study. Eur J Cancer 169:198–209. https://doi.org/10.1016/j.ejca.2022.04.010
Mo S, Ye L, Wang D, Han L, Zhou S, Wang H, Dai W, Wang Y, Luo W, Wang R, Xu Y, Cai S, Liu R, Wang Z, Cai G (2023) Early detection of molecular residual disease and risk stratification for stage I–III colorectal cancer via circulating tumor DNA methylation. JAMA Oncol 9(6):770. https://doi.org/10.1001/jamaoncol.2023.0425
Nakamura Y, Watanabe J, Akazawa N, Hirata K, Kataoka K, Yokota M, Kato K, Kotaka M, Kagawa Y, Yeh K-H, Mishima S, Yukami H, Ando K, Miyo M, Misumi T, Yamazaki K, Ebi H, Okita K, Hamabe A, Sokuoka H (2024) ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med 30(11):3272–3283. https://doi.org/10.1038/s41591-024-03254-6
Negro S, Pulvirenti A, Trento C, Indraccolo S, Ferrari S, Scarpa M, Bergamo E, Pucciarelli S, Deidda S, Restivo A, Lonardi S, Spolverato G (2025) Circulating tumor DNA as a real-time biomarker for minimal residual disease and recurrence prediction in stage II colorectal cancer: A systematic review and meta-analysis. Int J Mol Sci 26(6):2486. https://doi.org/10.3390/ijms26062486
Vojjala N, Gibatova V, Shah RN, Singal S, Prabhu R, Krishnamoorthy G, Riggins K, Moka N (2025) Integrating circulating tumor DNA into clinical management of colorectal cancer: Practical implications and therapeutic challenges. Cancers 17(15):2520. https://doi.org/10.3390/cancers17152520
Oki E, Kotani D, Nakamura Y, Mishima S, Bando H, Yukami H, Ando K, Miyo M, Watanabe J, Hirata K, Akazawa N, Yeh K-H, Laliotis G, Sharma S, Liu M, Taniguchi H, Takemasa I, Kato T, Mori M, Yoshino T (2023) Circulating tumor DNA dynamics as an early predictor of recurrence in patients with radically resected colorectal cancer: Updated results from GALAXY study in the CIRCULATE-Japan. J Clin Oncol 41(16suppl):3521. https://doi.org/10.1200/jco.2023.41.16_suppl.3521
Parikh AR, Chee BH, Tsai J, Rich TA, Price KS, Patel SA, Zhang L, Ibrahim F, Esquivel M, Van EE, Jarnagin JX, Raymond VM, Corvera CU, Hirose K, Nakakura EK, Corcoran RB, Loon KV, Atreya CE (2024) Minimal residual disease using a plasma-only circulating tumor DNA assay to predict recurrence of metastatic colorectal cancer following curative intent treatment. Clin Cancer Res 30(14):2964–2973. https://doi.org/10.1158/1078-0432.ccr-23-3660
Roshandel G, Ghasemi-Kebria F, Malekzadeh R (2024) Colorectal cancer: Epidemiology, risk factors, and prevention. Cancers 16(8):1530. https://doi.org/10.3390/cancers16081530
Sanz-Garcia E, Peinado P, Peláez A, Lopez-Aranda EG, Álvarez-Gallego R, Muñoz C, Toledano C, Mihic L, Ortega J, Lazaro A, Montesino BM, Bressel C, Gonzalo A, Hernando O, Lopez M, Rubio C, Fabra I, Quijano Y, Vicente E, Cubillo A (2025) Circulating tumor DNA using a plasma-only assay predicts survival in patients with oligometastatic colorectal cancer after definitive therapy. J Gastrointest Oncol 16(2):580–590. https://doi.org/10.21037/jgo-24-819
Sinicrope FA, Segovia DI, Hardin A, Rich TA, Alberts SR, Shi Q (2025) Tissue-free circulating tumor DNA assay and patient outcome in a phase III trial of FOLFOX-based adjuvant chemotherapy (Alliance N0147). J Clin Oncol 43(16suppl):3504. https://doi.org/10.1200/jco.2025.43.16_suppl.3504
Suzuki T, Suzuki T, Yoshimura Y, Yahata M, Yew PY, Nakamura T, Nakamura Y, Park J-H, Matsuo R (2020) Detection of circulating tumor DNA in patients of operative colorectal and gastric cancers. Oncotarget 11(34):3198–3207. https://doi.org/10.18632/oncotarget.27682
Tie J, Cohen JD, Lahouel K, Lo SN, 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 (2022) Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 386(24):2261–2272. https://doi.org/10.1056/nejmoa2200075
World Cancer Research Fund (2025), July 28 Colorectal cancer statistics. World Cancer Research Fund. https://www.wcrf.org/preventing-cancer/cancer-statistics/colorectal-cancer-statistics/
World Health Organization (2023), July 11 Colorectal cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer/
Yukami H, Nakamura Y, Mishima S, Ando K, Bando H, Watanabe J, Hirata K, Akazawa N, Ikeda M, Yokota M, Kato K, Laliotis G, Aushev VN, Jurdi AA, Liu M, Kotani D, Oki E, Takemasa I, Kato T, Yoshino T (2024) Circulating tumor DNA dynamics in patients with colorectal cancer with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN. J Clin Oncol 42(3suppl):6. https://doi.org/10.1200/jco.2024.42.3_suppl.6
Zheng J, Qin C, Wang Q, Tian D, Chen Z (2024) Circulating tumor DNA–based molecular residual disease detection in resectable cancers: A systematic review and meta-analysis. EBioMedicine 103:105109. https://doi.org/10.1016/j.ebiom.2024.105109

The authors declare no competing interests.

Download PDF

Version 1

posted

You are reading this latest preprint version

Using ctDNA to Predict Recurrence After Surgery in Stage II–III Colorectal Cancer: A Systematic Review and Narrative Meta-Analysis

Status:

Version 1

Abstract

Figures

Introduction

Research Gap

Study Objectives

Methodology

Results

Discussion

Conclusion

Limitations

Risk of Bias Assessment

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1