Early Detection vs. Overdiagnosis: The ctDNA Screening Paradox

The promise of circulating tumor DNA for early cancer detection comes with a complex paradox: the very sensitivity that makes ctDNA valuable for catching cancer early also raises concerns about overdiagnosis and overtreatment. As Dr. Gabriela Rosu, Veristat’s Vice President, Global Medical Affairs, cautions, "Unfortunately, not all cancers have reliable screening methods. And right now, we cannot say that ctDNA is completely cleared to be a screening method in all malignancies and all patients, not yet."

This measured assessment reflects the sophisticated understanding required to navigate the screening paradox that could define the future of cancer care.

The Instagram Influencer Problem

Dr. Rosu highlights a concerning trend: "We see people doing full body scans because it's fancy. Some actors are doing that on Instagram promoting one method or another. What they don’t understand is that, while yes, this is a great snapshot of what is happening at the moment, it does not mean that tomorrow or next week things will be the same.  These investigations should be medically driven and not promoted on social media as a trend."

This observation points to a broader challenge in medical innovation—the gap between technological capability and clinical wisdom. Just because we can detect molecular traces of potential cancer doesn't mean we should, especially without understanding the clinical implications.

The CCGA study, one of the largest efforts to validate ctDNA screening, demonstrated the complexity of this challenge. While the whole genome methylation assay performed best and could detect cancer across multiple types with high specificity, it also identified "cancer-like" signals in approximately 1% of apparently healthy individuals (false positives). Follow-up revealed that some of these cases did indeed develop cancer months later, but others remain unexplained. And while 1% is indeed a small number, when screening millions of individuals, that number becomes significant, and we need to understand very well what causes these false-positive results.

The Biology of Natural Cancer Surveillance

Dr. Rosu explains a fundamental biological reality: "We all start several cancers in our lives and the immune system destroys them." This insight reveals why ctDNA screening is so complex—our immune systems are constantly identifying and eliminating abnormal cells.

"There are always going to be aberrant cells starting to develop somewhere. You have a place with a lot of inflammation. There are going to be mutations or aberrant cells that are going to shed DNA in the bloodstream. Is that cancer every time? No."

This natural process of cancer initiation and immune elimination creates a biological background that ctDNA assays must navigate. The challenge isn't just technical sensitivity—it's distinguishing between:

• Transient cellular abnormalities that will be naturally eliminated

• Early cancers that require intervention

• Indolent processes that may never become clinically significant

The BRCA Paradigm: When Screening Makes Sense

Dr. Rosu provides important context about when screening can be justified: "BRCA mutation is a very powerful mutation inducing cancer. So I think it's good to know because these patients can make some life-saving decisions."

The BRCA example illustrates key principles for appropriate screening:

• High Penetrance: BRCA1/2 mutation carriers have an estimated 45–85% lifetime risk of developing breast cancer.

• Actionable Results: Positive results lead to proven interventions (prophylactic surgery, enhanced surveillance)

• Informed Decision-Making: Patients can weigh risks and benefits with their healthcare providers

The emotional and reproductive implications of genetic information require careful consideration.

The Current State of ctDNA Screening

Several large-scale studies are exploring ctDNA screening applications:

The STRIVE Study: Enrolling 120,000 women, this study expanded from breast cancer screening to include multiple cancer types. Early results suggest promise for detecting aggressive cancers while potentially avoiding detection of indolent disease.

The ECLIPSE Trial: This study is evaluating the LUNAR test, which combines somatic genomic variants with epigenomic analysis. The approach achieved 94% specificity in early-stage colorectal cancer, with enhanced sensitivity when methylation data was included.

AI-EMERGE: This retrospective study of 817 plasma samples used machine learning to achieve 85% sensitivity and 85% specificity for early-stage colorectal cancer detection.

The Overdiagnosis Dilemma

The concept of overdiagnosis—detecting cancers that would never become clinically significant—is particularly relevant for ctDNA screening. This biological reality creates several challenges:

Lead-Time Bias: Detecting cancer earlier doesn't necessarily improve outcomes if the cancer would have been successfully treated when clinically apparent.

Treatment Burden: Earlier detection may lead to more aggressive treatment for cancers that might have remained indolent.

Psychological Impact: Positive screening results create anxiety and may affect quality of life even when treatment is successful.

A Framework for Responsible Implementation

Dr. Rosu suggests a measured approach: "Hopefully it's going to be soon and in conjunction with other investigations like imaging, clinical information and medical history as well as genetic insight, so it’s basically putting everything together in a focused, driven manner."

This integrated approach suggests several principles for responsible ctDNA screening:

Risk Stratification: Focus screening on populations with elevated cancer risk based on genetics, family history, or environmental exposures.

Multi-Modal Integration: Combine ctDNA results with imaging, clinical assessment, and other biomarkers before making treatment decisions.

Temporal Monitoring: Use longitudinal ctDNA patterns rather than single time points to distinguish persistent from transient signals.

Informed Consent: Ensure patients understand both the benefits and limitations of ctDNA screening, including the possibility of false positives and overdiagnosis.

The Path Forward

Dr. Rosu's vision for the future is optimistic but cautious: "We're going to be able to screen these patients better and prevent advanced disease because I think you know a lot of cancers are curable if they're detected early."

The key is implementing screening programs that maximize benefits while minimizing harms:

Validation in Diverse Populations: Current studies are expanding to include diverse ethnic and geographic populations to ensure broad applicability.

Clinical Utility Studies: Beyond analytical validation, studies must demonstrate that ctDNA screening actually improves patient outcomes.

Health Economics: Understanding the cost-effectiveness of ctDNA screening is crucial for healthcare system adoption.

Regulatory Framework: The FDA's recent guidance on ctDNA biomarker development provides a pathway, but implementation requires careful attention to intended use and clinical context.

The Promise and the Responsibility

The enthusiasm for ctDNA screening is understandable—the technology offers unprecedented ability to detect cancer at its earliest stages. However, as Dr. Rosu wisely cautions, we must "judge this medically" rather than being swayed by technological excitement alone.

The goal isn't just to detect cancer earlier, but to improve patient outcomes while minimizing unnecessary intervention. This requires sophisticated understanding of cancer biology, careful study design, and thoughtful implementation that puts patient welfare above technological capability.

As we navigate this paradox, the measured approach advocated by clinical researchers like Dr. Rosu provides important guidance: embrace the potential of ctDNA screening while maintaining the clinical wisdom to implement it responsibly.

At Veristat, we help sponsors move innovation from concept to clinic. With deep scientific expertise, regulatory know-how, and global trial experience, we design and deliver studies, whether ctDNA-driven, biomarker-guided, or built around novel endpoints that withstand scrutiny and accelerate success. From protocol design and assay strategy to data interpretation and regulatory engagement, we bridge innovation to implementation. If you’re ready to explore how Veristat can help transform your oncology development program.

Learn More:

• Trends in Oncology Regulation: FDA Draft Guidance on OS and Radiopharmaceuticals

• From Clinical Strategy to Patient Impact: 5 Lessons from Cindy Henderson

• Accelerate Your Oncology Therapy Breakthroughs with Veristat