Circulating tumor DNA (ctDNA) is gaining traction as a powerful biomarker in oncology, providing a non-invasive means to monitor disease burden, assess treatment response, and potentially guide earlier intervention. As data accumulates across trials and technologies, ctDNA is emerging not just as a tool for personalized cancer care, but also as a potential early endpoint in clinical trials, an innovation that could accelerate drug development and regulatory decision-making.

The U.S. Food and Drug Administration has recognized this potential, noting in its draft guidance that ctDNA may serve as an early surrogate marker “reasonably likely to predict clinical benefit” in early-stage solid tumor drug development. However, questions remain around pre-clinical requirements, assay variability, tumor and stage-specific biology, and the broader need for data harmonization across technologies and cancer types.

To explore these challenges and opportunities, Drug Discovery News spoke with Gary Pestano, Chief Development Officer at Biodesix, and Stephen Kulisch, Vice President of Product Marketing at Bio-Rad Laboratories. They shared their perspectives on the state of ctDNA in clinical care and drug development, the value of real-time monitoring, and the steps needed to integrate ctDNA more fully into precision oncology and regulatory frameworks.

Can you explain what ctDNA is, and why it’s becoming such an important tool in cancer research and care?

ctDNA refers to fragments of DNA that are shed by cancer cells into the bloodstream. It is a subset of circulating free DNA (cfDNA) that may be released actively or from dying (apoptotic) cells. Because ctDNA carries genetic information specific to the tumor, it provides a non-invasive way to gain real-time insights into the molecular characteristics of a patient’s cancer.

ctDNA is typically obtained via liquid biopsy, which involves a simple blood draw, and offers significant advantages over traditional tissue biopsies. It minimizes patient discomfort, reduces procedural risk, and allows for repeated sampling, making it ideal for ongoing monitoring.

In cancer research and care, ctDNA is becoming increasingly valuable. Its levels have been shown to correlate with tumor burden and are often prognostic of patient outcomes following therapy. Importantly, ctDNA analysis can help detect actionable genetic mutations, monitor disease progression, assess treatment response, and identify minimal residual disease (MRD) or early relapse. This dynamic and accessible biomarker is helping to advance precision oncology by enabling more informed, adaptive, and personalized treatment strategies.

What kind of information can ctDNA give us about a patient’s cancer that traditional imaging or biopsies might miss?

ctDNA can provide critical information about a patient’s cancer that traditional imaging or tissue biopsies may miss. While imaging offers a structural view and tissue biopsies typically analyze a small, localized sample, ctDNA reflects a broader and more dynamic molecular snapshot by capturing tumor DNA fragments shed into the bloodstream from various sites of disease.

This allows ctDNA to reveal tumor heterogeneity, including the presence of multiple subclones or emerging resistance mutations, which may not be detected in a single biopsy. It also enables non-invasive, quantitative monitoring of disease progression or remission over time, including the detection of minimal or MRD—often months earlier than what imaging can detect.

By identifying subtle molecular changes, ctDNA supports early detection of relapse, real-time assessment of treatment response, and the emergence of resistance mechanisms. This makes it a powerful tool to guide precision treatment strategies and improve patient outcomes throughout the cancer care continuum.

What is the ctDNA to Monitor Treatment Response (ctMoniTR) Project and why was it launched? 

ctDNA shows strong potential as a tool for measuring treatment efficacy in clinical trials. Friends of Cancer Research launched the ctMoniTR Project to create a unified approach for generating the data needed to support ctDNA’s use as an early endpoint for treatment response in regulatory decision-making. By validating ctDNA as a reliable endpoint, we can accelerate the development of effective cancer therapies and help bring them to patients faster. 

Droplet Digital PCR (ddPCR) was used in this study. What makes ddPCR a strong choice for this kind of work, especially compared to other ctDNA detection methods?

ddPCR is a powerful tool for detecting ctDNA, particularly when sensitivity, precision, and practicality are critical. ddPCR partitions each sample into thousands of droplets, allowing for absolute quantification of target molecules in precise and reproducible manner without the need for standard curves. This makes it especially effective for identifying rare ctDNA variants in a background of abundant wild-type cfDNA, an essential capability for liquid biopsy applications.

Compared to next-generation sequencing (NGS), ddPCR offers several practical advantages: it has a faster turnaround time, simpler workflows, lower bioinformatics demands, and is generally more cost-effective, especially for repeat monitoring. 

These features make ddPCR not only a technically robust option, but also a more scalable and accessible technology for clinical oncology, particularly in decentralized or resource-limited settings around the world, where implementing an NGS testing infrastructure may be challenging.

 What were the key findings of the ctMoniTR study, and why do they represent an important step forward in ctDNA monitoring?

The latest phase of the ctMoniTR project, published in Clinical Cancer Research, found that when patients with advanced non-small cell lung cancer (aNSCLC) were treated with tyrosine kinase inhibitors (TKIs), those whose ctDNA levels dropped to undetectable levels within 10 weeks had better overall survival (OS) and stayed disease-free for longer¹.

What sets this study apart is its scale and design. Unlike earlier efforts that focused on individual case studies or small cohorts, this analysis pooled patient-level data from eight clinical studies, spanning five different ctDNA assays, including four NGS-based and one ddPCR-based test. This aggregation provides robust, real-world evidence across diverse testing platforms.

These findings add to the growing body of research showing that changes in ctDNA levels during treatment reflect clinical outcomes. Crucially, the study also recommends that future prospective trials incorporate predefined molecular response thresholds, helping to advance ctDNA as a validated early endpoint for assessing treatment efficacy in cancer care.

Were there particular types of therapies or cancers where ctDNA was especially predictive of response or resistance?

ctDNA has shown the greatest utility in TKI treatment and most data has been generated in the relatively mutation-rich solid tumor NSCLC, particularly with epidermal growth factor receptor (EGFR) TKIs.

Ongoing studies are expanding ctDNA’s role in tracking other molecular markers, such as targeted mutations in the KRAS, ESR1, BRAF and AKT genes, and also broadly for immune-therapies.  

Beyond lung cancer, ctDNA has also demonstrated value in bladder, breast, prostate, and head and neck squamous cell carcinoma, supporting its broader potential across different cancer types and treatment strategies².

Looking ahead, how close is ctDNA use as a routine tool in cancer care, not just research? What are the remaining barriers?

We’re steadily moving toward the routine use of ctDNA in cancer care, particularly for monitoring treatment response and detecting MRD. Clinical guidelines from major organizations including the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the Association for Molecular Pathology, and the European Society for Medical Oncology already recommend ctDNA testing for specific diagnostic and treatment decisions in certain cancer types.

Technological progress is driving this shift forward. Improvements such as deeper sequencing, high-sensitivity methods like ddPCR, and more robust bioinformatics pipelines are making ctDNA assays more reliable. At the same time, collaborative efforts led by groups like Friends of Cancer Research, the Foundation for the National Institutes of Health, and the Blood Profiling Atlas in Cancer are helping establish standards and build consensus among key stakeholders.

Still, there are important barriers to overcome. These include the need to harmonize how we assess test sensitivity and specificity, especially at low detection limits and across different testing platforms, and to address biological variables like clonal hematopoiesis of indeterminate potential (CHIP). There's also a need to standardize pre-analytical procedures, such as blood collection timing and tube types, and to integrate ctDNA data with traditional tissue biopsies and imaging results.

Overall, broader adoption will depend on generating high-quality clinical evidence and metadata that demonstrate how ctDNA can best be used across various cancers and stages of disease.

What are some of the most exciting advances in ctDNA for MRD monitoring today?

Exciting advances in ctDNA and MRD monitoring are expanding the role of precision oncology. Innovations include the development of ultra-sensitive assays, such as digital PCR, and the integration of DNA methylation analysis, fragmentomics, and broader next-generation sequencing (NGS) panels. These tools enable more comprehensive baseline profiling, allowing clinicians to identify a wider range of markers and establish more robust surrogate indicators for cancer recurrence and remission.

Together, these technologies are making it possible to detect MRD earlier and more accurately, guide treatment decisions with greater precision, and monitor response across all stages of cancer, all in a way that is increasingly cost-effective and feasible for routine clinical use.

How might real-time ctDNA monitoring impact the way new cancer therapies are developed and evaluated?

Near real-time ctDNA monitoring has the potential to transform cancer therapy development by providing a non-invasive, cost-effective, and early indicator of treatment response. By tracking changes in tumor-derived DNA in the blood over time, researchers and clinicians can rapidly assess whether a therapy is working, identify emerging resistance mechanisms, and better predict patient outcomes.

With the growing sensitivity and specificity of current technologies, alongside standardized lab protocols, quality controls, and defined thresholds, ctDNA could support more personalized treatment strategies, enable earlier intervention or discontinuation of ineffective therapies, and allow for faster clinical trial readouts compared to traditional imaging or endpoint-based approaches. This would streamline drug development and help bring effective therapies to patients more quickly.

References:

1. Andrews, H. S. et al. ctDNA Clearance as an Early Indicator of Improved Clinical Outcomes in Advanced NSCLC Treated with TKI: Findings from an Aggregate Analysis of Eight Clinical Trials. Clinical Cancer Research OF1–OF11 (2025).
2. McKelvey, B. A. et al. Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages. Diagnostics 14, 912 (2024).