In a new article at npj Precision Oncology, Bartolomucci et al. comprehensively review the use of ctDNA for monitoring therapeutic response.
https://www.nature.com/articles/s41698-025-00876-y
The abstract is brief:
- Circulating tumor DNA (ctDNA) has emerged as a dynamic biomarker in cancer, as evidenced by its increasing integration into clinical practice. Carrying tumor specific characteristics, ctDNA can be used to inform treatment selection, monitor response, and identify drug resistance.
- In this review, we provide a comprehensive, up-to-date summary of ctDNA in monitoring treatment response with a focus on lung, colorectal, and breast cancers, and discuss current challenges and future directions.
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AI CORNER
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Given the brief abstract, a longer summary by Chat GPT 4o.
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Here’s a blog-ready article that serves as a detailed TL;DR of the new review paper by Bartolomucci et al., published in NPJ Precision Oncology in 2025:
TL;DR: Circulating Tumor DNA (ctDNA) to Monitor Treatment Response in Solid Tumors
A comprehensive new review by Bartolomucci et al. (NPJ Precision Oncology, 2025) offers one of the most in-depth, up-to-date examinations of how circulating tumor DNA (ctDNA) is transforming the way we monitor treatment response, resistance, and minimal residual disease (MRD) across solid tumors. The paper systematically explores ctDNA’s utility in lung, colorectal, and breast cancers, while highlighting key methodologies, clinical trials, and future directions.
🔬 What’s ctDNA and Why Does It Matter?
ctDNA refers to tumor-derived DNA fragments found in the blood, offering a non-invasive, real-time molecular snapshot of tumor dynamics. Unlike traditional imaging or tissue biopsies, ctDNA can:
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Reflect systemic disease, including metastases.
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Provide early insight into treatment efficacy or failure.
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Detect residual disease and emerging resistance mutations long before clinical progression.
The authors argue that ctDNA is best positioned right now to serve as a treatment response tool, even more than for early detection or initial diagnostics.
🧪 Techniques and Tools
The review outlines two broad categories of ctDNA detection:
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Targeted assays: PCR-based methods (qPCR, dPCR, BEAMing) to detect known mutations (e.g., EGFR, KRAS).
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NGS-based assays: Broader approaches (e.g., CAPP-Seq, Safe-SeqS, Duplex Sequencing, CODEC) capable of detecting unknown or low-frequency variants.
Emerging areas include:
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Methylation profiling
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Fragmentomics (size, end motifs, nucleosome positioning)
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Multi-analyte liquid biopsy (e.g., integrating CTCs, EVs, ctDNA)
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Non-plasma biofluids: urine, saliva, CSF
🫁 Lung Cancer: Leading the Way
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FDA has approved multiple ctDNA-based tests for NSCLC (e.g., Cobas EGFR, Guardant360, FoundationOne Liquid CDx).
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ctDNA has shown strong correlation with tumor burden, MRD, and response to EGFR/ALK inhibitors and immune checkpoint therapies.
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Studies like TRACERx, APPLE, and BR.36 highlight how ctDNA dynamics can guide treatment selection and timing, even predicting progression before RECIST imaging criteria show changes.
🦠 Colorectal Cancer: A Model for MRD Detection
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ctDNA is highly sensitive in CRC, especially post-surgery, for detecting MRD and recurrence risk.
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In stage II CRC, ctDNA positivity post-resection strongly predicts recurrence, guiding adjuvant therapy decisions.
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In stage III CRC, ctDNA clearance correlates with survival, and persistent ctDNA flags treatment failure.
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In metastatic CRC, ctDNA tracks drug resistance (e.g., RAS mutations after anti-EGFR therapy) and is being tested for guiding rechallenge strategies.
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Trials like CIRCULATE-US, TRACC, and DYNAMIC are helping define ctDNA's role in personalized CRC management.
🎗 Breast Cancer: Emerging Applications
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ctDNA tracks treatment response in neoadjuvant and metastatic settings, especially in triple-negative and HR+/HER2- subtypes.
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Studies show ctDNA can predict relapse even in patients with a pathologic complete response.
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Trials like SOLAR-1 have helped secure ctDNA-driven FDA approvals (e.g., alpelisib for PIK3CA mutations).
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ctDNA is also being used to track ESR1 mutations and guide hormone therapy adjustments (e.g., PADA-1 trial).
🚧 Challenges Ahead
Despite the promise, ctDNA still faces real-world barriers:
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Low abundance in early-stage or low-shedding tumors.
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Technical variation and lack of assay standardization.
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Confounding from CHIP (clonal hematopoiesis).
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Cost and turnaround time of NGS-based assays.
📈 Final Takeaway
This review makes a compelling case that ctDNA is no longer just an experimental tool—it's an increasingly clinical-grade biomarker for monitoring cancer treatment, particularly in lung, colorectal, and breast cancers. With growing clinical trial evidence and technical innovations (e.g., CODEC sequencing, fragmentomics, and methylation-based detection), ctDNA may soon become a standard of care in precision oncology.
📄 Read the full paper: doi.org/10.1038/s41698-025-00876-y
Let me know if you’d like a version with bullet points, or with a different tone for your audience.
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The paper also notes that multimodal panels are starting to bridge the gap, combining mutation analysis, methylation, fragmentomics, and sometimes expression signals—blurring the line between bespoke and off-the-shelf testing.
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Do they address concerns that MDR treatment monitoring doesn't perhaps really improve patient outcomes? That it just makes everybody's PFS half as long?
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Great question—and yes, the paper does acknowledge that concern, albeit somewhat indirectly and diplomatically.
In discussing Minimal Residual Disease (MRD) detection using ctDNA, the authors point out that:
“Although most ctDNA studies to date have been observational in nature, the potential role of ctDNA monitoring to help guide clinical decision-making cannot be overlooked.”
This signals an important limitation: we still lack definitive evidence that ctDNA-guided MRD detection and early intervention actually improve overall survival (OS) or quality of life. The authors do not shy away from this and emphasize that randomized interventional trials are ongoing to address this gap.
They also highlight:
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That ctDNA-positive patients often relapse, but it's unclear whether earlier detection and treatment change the ultimate outcome or merely start the clock earlier, shortening PFS without improving OS.
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The CIRCULATE-US, PEGASUS, and DYNAMIC trials are specifically designed to test whether ctDNA-driven escalation or de-escalation of therapy leads to meaningful benefits.
So while the tone is optimistic about ctDNA’s future, the review is careful not to overstate current clinical utility and calls for stronger evidence from prospective trials to justify acting on MRD signals. [On which theme see Normanno.]
