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

Abstract

Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for minimal residual disease (MRD) in CRC patients. Recent studies have shown that the ability to detect MRD using ctDNA assay after curative-intent surgery will change how to assess the recurrence risk and patient selection for adjuvant chemotherapy. We performed a meta-analysis of post-operative ctDNA in stage I–IV (oligometastatic) CRC patients after curative-intent resection. We included 23 studies representing 3568 patients with evaluable ctDNA in CRC patient post-curative-intent surgery. Data were extracted from each study to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I–III and oligometastatic stage IV CRC patients. Results showed that the pooled hazard ratio (HR) for recurrence-free survival (RFS) in post-surgical ctDNA-positive versus -negative patients in all stages was 7.27 (95% CI 5.49–9.62), p < 0.00001. Subgroup analysis revealed pooled HRs of 8.14 (95% CI 5.60–11.82) and 4.83 (95% CI 3.64–6.39) for stages I–III and IV CRC, respectively. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA-positive versus -negative patients in all stages was 10.59 (95% CI 5.59–20.06), p < 0.00001. Circulating tumor DNA (ctDNA) analysis has revolutionized non-invasive cancer diagnostics and monitoring, with two primary forms of analysis emerging: tumor-informed techniques and tumor-agnostic or tumor-naive techniques. Tumor-informed methods involve the initial identification of somatic mutations in tumor tissue, followed by the targeted sequencing of plasma DNA using a personalized assay. In contrast, the tumor-agnostic approach performs ctDNA analysis without prior knowledge of the patient’s tumor tissue molecular profile. This review highlights the distinctive features and implications of each approach. Tumor-informed techniques enable the precise monitoring of known tumor-specific mutations, leveraging the sensitivity and specificity of ctDNA detection. Conversely, the tumor-agnostic approach allows for a broader genetic and epigenetic analysis, potentially revealing novel alterations and enhancing our understanding of tumor heterogeneity. Both approaches have significant implications for personalized medicine and improved patient outcomes in the field of oncology. The subgroup analysis based on the ctDNA method showed pooled HRs of 8.66 (95% CI 6.38–11.75) and 3.76 (95% CI 2.58–5.48) for tumor-informed and tumor-agnostic, respectively. Our analysis emphasizes that post-operative ctDNA is a strong prognostic marker of RFS. Based on our results, ctDNA can be a significant and independent predictor of RFS. This real-time assessment of treatment benefits using ctDNA can be used as a surrogate endpoint for the development of novel drugs in the adjuvant setting.

SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications – review article

“…Moreover, advancements in big data and biotechnology have unlocked the potential for precision medicine, even at the individual level. Prognostic markers and circulating tumor DNA have emerged as promising adjunct tools for predicting outcomes in neoadjuvant or adjuvant chemotherapy scenarios 116 , 117 . Looking ahead, the evolution of comprehensive management integrating conventional surgical approaches with precision medicine signifies a pivotal development direction for surgeons.…”

Harnessing Minimal Residual Disease as a Predictor for Colorectal Cancer: Promising Horizons Amidst Challenges

“…Typically, in the context of a "curative" therapeutic approach and complete remission (CR) confirmed through routine diagnostic means, the MRD is considered when the need arises to validate the true or deeper extent of the achieved CR. Such instances might include (1) postoperative assessment after curative resection for stages I-III CRC [21], (2) evaluation of post-curative resection (R0) for stage IV CRC [22,23], (3) locally advanced CRC achieving clinical CR after neoadjuvant therapy (NAT) [24], (4) MSI-H CRC showing no tumor activity after immunotherapy [25], and (5) clinical judgment of CR in mCRC patients after systemic treatment. We will discuss another consideration: how ctDNA can assist in identifying treatment targets in advanced stage mCRC patients.…”

“…The proliferation of MRD studies has generally yielded positive research conclusions, but significant disparities persist among concerning MRD detection methods and interpretation criteria. MRD detection based on Next-Generation Sequencing (NGS) is predominantly divided into two prominent streams: Tumor-informed and Tumor-naïve [21]. These approaches exhibit competitive attributes in terms of sensitivity and specificity due to reliance or independence on primary tumor tissue, use of custom or fixed panels, and variation in assessment periods.…”

Editorial: The emerging role of liquid biopsy in gastrointestinal, pancreatic and liver cancers

“…Colorectal cancer is the first solid tumor where the concept of minimal residual disease (MRD) lead to a change in clinical practice ( 6 ). Since 2022, ctDNA testing after surgery has been approved by Medicare, the main insurer in the United States.…”