What is the role of liquid biopsy in medical gastroenterology for detecting and monitoring gastrointestinal cancers?

Liquid Biopsy in Medical Gastroenterology

Liquid biopsy is an emerging minimally invasive diagnostic tool in gastroenterology that analyzes circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) from blood samples, primarily used for advanced gastrointestinal cancers when traditional tissue biopsy is not feasible or for disease monitoring. 1

Core Components of Liquid Biopsy

The "tumor circulome" encompasses several analyzable biomarkers 1:

• Circulating tumor DNA (ctDNA): Tumor-derived DNA fragments shed into bloodstream 1
• Circulating tumor cells (CTCs): Intact cancer cells detached from primary or metastatic sites 1, 2
• Extracellular vesicles (EVs): Lipid-bound particles containing tumor-derived RNA, DNA, and proteins 1
• Cell-free DNA (cfDNA) and circulating tumor RNA (ctRNA): Additional genetic material for analysis 1, 3

Clinical Applications in Gastroenterology

Gastric Cancer

The NCCN guidelines (2022) recommend liquid biopsy using validated NGS-based comprehensive genomic profiling in CLIA-approved laboratories for patients with advanced or metastatic gastric cancer who cannot undergo traditional biopsy or for disease progression monitoring. 1

Specific indications include 1:

• Biomarker identification: Detection of HER2/ERBB2 amplification, MSI status, MMR deficiency, TMB-H, and NTRK gene fusions when tissue is limited
• Treatment selection: 69% of advanced gastroesophageal adenocarcinoma patients showed ≥1 targetable alteration by ctDNA NGS analysis 1
• Disease surveillance: Real-time monitoring in patients unable to undergo repeat tissue biopsies 1

Critical caveat: A negative liquid biopsy result must be interpreted with caution, as it does not exclude the presence of tumor mutations or amplifications 1

Colorectal Cancer

Liquid biopsy applications in colorectal cancer include 1, 2:

• Mutation detection: Identification of KRAS, NRAS, BRAF, and PIK3CA mutations to predict anti-EGFR therapy response
• Early relapse detection: ctDNA can identify recurrence before clinical or radiographic evidence 1
• Real-time molecular evolution: Tracking tumor mutations during targeted therapy that may not be present in original tissue biopsy 1

Hepatocellular Carcinoma (HCC)

Alpha-fetoprotein (AFP), once recommended by AASLD and EASL guidelines, is no longer recommended for HCC screening due to poor sensitivity (only elevated in 40-60% of cases) and specificity issues. 1 Current guidelines do not recommend AFP or any other single biomarker for HCC diagnosis 1

Technical Considerations

Testing Methodology

When tissue is limited or biopsy is not feasible 1:

1. First-line approach: IHC, in situ hybridization (ISH), or targeted PCR for specific biomarkers
2. Comprehensive profiling: NGS-based assays performed in CLIA-approved laboratories for broader genomic analysis
3. Validation requirement: Only validated assays should be used for clinical decision-making 1

Advantages Over Tissue Biopsy

Liquid biopsy offers several benefits 2, 3, 4:

• Minimally invasive: Simple blood draw versus surgical/endoscopic procedures
• Addresses tumor heterogeneity: Captures genetic material from multiple tumor sites and metastases 1, 5
• Serial monitoring: Can be repeated frequently without patient risk 3, 6
• Real-time assessment: Reflects current tumor biology rather than historical tissue sample 1, 5

Current Limitations and Pitfalls

Sensitivity Issues

The major limitation is that liquid biopsy sensitivity varies significantly by cancer stage, tumor burden, and biomarker type. 4, 5, 6

Key concerns include 1, 3, 5:

• Early-stage detection: Lower sensitivity in early-stage disease when tumor burden is minimal
• False negatives: Absence of detectable ctDNA does not rule out cancer presence 1
• Standardization gaps: Lack of universal protocols for sample processing, analysis, and interpretation 1, 5

Clinical Context

Liquid biopsy is currently most appropriate for advanced disease settings, particularly when traditional biopsy is contraindicated or for longitudinal monitoring. 1, 2

It should not replace tissue biopsy when 1, 4:

• Adequate tissue can be safely obtained
• Initial diagnosis and staging are required
• Histologic subtype classification is needed for treatment planning

Future Directions

Emerging applications under investigation include 1, 4, 6:

• Cancer screening: Early detection in high-risk populations
• Minimal residual disease monitoring: Post-treatment surveillance for microscopic disease
• Therapy response prediction: Identifying responders versus non-responders before clinical progression
• Extracellular vesicle analysis: RNA sequencing of tumor-derived EVs for comprehensive molecular profiling 1

The field requires well-designed prospective studies to establish clinical utility, standardized protocols, and cost-effectiveness before widespread adoption beyond current guideline-supported indications. 5, 6