Is cell-free DNA (cfDNA) used for cancer screening?

Cell-Free DNA for Cancer Screening

Yes, cell-free DNA (cfDNA) is used for cancer screening, though its clinical application remains limited primarily to specific FDA-approved contexts and clinical trials, with current technology showing promise but significant limitations for population-wide screening. 1, 2

Current FDA-Approved Clinical Applications

Cell-free DNA testing has achieved regulatory approval for three specific cancer applications:

• EGFR mutation detection in non-small cell lung cancer 1, 2
• PIK3CA mutation detection in breast cancer 1, 2
• SEPT9 promoter methylation testing for colorectal cancer 1, 2

These represent targeted molecular testing rather than broad screening applications. 1

Screening Performance Characteristics

Colorectal Cancer Screening

The most robust screening data comes from colorectal cancer, where a cfDNA blood-based test demonstrated:

• 83.1% sensitivity for detecting colorectal cancer 3
• 89.6% specificity for advanced neoplasia 3
• Only 13.2% sensitivity for advanced precancerous lesions—a critical limitation since early detection of precancerous lesions prevents over 90% of colorectal cancer deaths 3

Multi-Cancer Screening Approaches

Multi-target assays like CancerSEEK show broader potential:

• 70% analytical sensitivity across eight cancer types 1
• >99% specificity for cancer detection 1
• 83% accuracy in localizing tumor to one of two anatomic sites 1

However, when cfDNA is used alone for pancreatic cancer screening, sensitivity is only 30%, increasing to 64% when combined with CA-19-9 and five additional protein biomarkers. 1, 2

Critical Limitations for Screening

The National Comprehensive Cancer Network and American College of Medical Genetics emphasize that cfDNA testing is most effective when combined with other biomarkers rather than as a standalone screening test. 2

Key barriers include:

• Highly variable cfDNA levels between patients limit applicability across cancer types 1
• Low sensitivity for early-stage disease and precancerous lesions—precisely when screening has greatest mortality benefit 1, 3
• Lack of standardization in collection, processing, and storage practices across institutions, resulting in genotyping error rates of 6.09% in multi-center studies 1
• Technical challenges including PCR bias, low read coverage, and SNP interference requiring specialized expertise 2

Clinical Context and Recommendations

The American College of Medical Genetics recommends cfDNA testing be performed at academic tertiary centers with specialized expertise and proper quality control measures. 2

The National Cancer Institute emphasizes that clinical applications are expanding from monitoring advanced metastatic cancer (where cfDNA concentrations are high) toward early-stage cancer detection and relapse monitoring (where concentrations are much lower and technical challenges multiply). 1

Where cfDNA Excels Beyond Screening

Cell-free DNA has proven more valuable for:

• Monitoring treatment response through longitudinal sampling 1
• Detecting acquired resistance mutations in real-time 4
• Identifying tumor evolution and disease recurrence 1
• Overcoming intratumoral heterogeneity limitations of tissue biopsies 1

In some cases, cfDNA has identified mutations years before cancer diagnosis, demonstrating potential for future screening applications as technology improves. 1

Practical Approach

For current clinical practice:

• Use FDA-approved cfDNA assays only for their specific approved indications (EGFR, PIK3CA, SEPT9) 1, 2
• Do not rely on cfDNA alone for cancer screening—combine with established biomarkers and imaging 1, 2
• Recognize that cfDNA blood tests cannot replace colonoscopy for colorectal cancer screening due to poor sensitivity for precancerous lesions 3
• Consider cfDNA primarily for monitoring in patients with established cancer rather than population screening 1, 4
• Ensure proper specimen handling following NCI biospecimen evidence-based best practices to minimize preanalytical errors 1

The field remains largely in clinical trial phases, with 1,370 active trials investigating cfDNA applications, but routine population-based cancer screening using cfDNA alone is not yet supported by evidence for mortality reduction. 4