What is the preferred initial diagnostic approach between Next-Generation Sequencing (NGS) testing and liquid biopsy for patients with lung adenocarcinoma?

Next-Generation Sequencing (NGS) Testing vs Liquid Biopsy for Lung Adenocarcinoma

Tissue-based NGS testing should be the preferred initial diagnostic approach for molecular profiling in patients with lung adenocarcinoma due to its superior sensitivity and comprehensive detection of actionable genetic alterations compared to liquid biopsy. 1

Rationale for Tissue-Based NGS as First Choice

Superior Detection of Actionable Mutations

• Tissue-based NGS demonstrates significantly higher sensitivity (94.8%) compared to liquid biopsy (52.6%) for detecting clinically relevant mutations and therapeutic targets 1
• Tissue testing can reliably detect all types of genetic alterations including:
  • Point mutations
  • Gene fusions/rearrangements (ALK, ROS1, RET, NTRK1/2/3)
  • MET exon 14 skipping mutations
  • Copy number variations

Comprehensive Molecular Profiling

• Current guidelines strongly recommend broad molecular profiling using NGS panels to identify all potentially actionable driver alterations 2
• A multiplex NGS approach is preferred over sequential single-gene testing to:
  • Preserve limited tissue
  • Reduce turnaround time
  • Increase cost-effectiveness 2
  • Identify rare but targetable alterations with frequencies ≤1% 2

Technical Considerations

• DNA and RNA-based NGS should be used complementarily:
  • DNA-based panels for mutations and copy number variations
  • RNA-based panels for better detection of gene fusions and alterations involving intronic regions (e.g., MET exon 14 skipping) 2
• A minimum of 20-30% tumor cells should be present in tested material to minimize false-negative results 2

Role of Liquid Biopsy

When to Consider Liquid Biopsy

• When tissue is insufficient or unavailable 2
• When repeat biopsies are needed to monitor treatment resistance 2
• When rapid results are needed (average 26.8 days faster than tissue testing) 3

Limitations of Liquid Biopsy

• Significantly lower sensitivity compared to tissue testing 1
• False negatives are common, particularly when tumor fraction is low (<1%) 4
• Important caveat: A negative liquid biopsy result should always be confirmed with tissue testing when possible 1, 2

Recommended Testing Algorithm

1. First-line approach: Tissue-based NGS testing using both DNA and RNA panels

   • Test for all established biomarkers: EGFR, ALK, ROS1, BRAF, MET, NTRK1/2/3, RET, KRAS G12C, HER2 2

2. If tissue is insufficient/unavailable: Proceed with liquid biopsy

   • If positive for actionable mutation → Initiate targeted therapy
   • If negative → Attempt tissue biopsy if clinically feasible 2, 1

3. For disease progression on targeted therapy: Consider both tissue rebiopsy and liquid biopsy to identify resistance mechanisms 2

Clinical Impact on Patient Outcomes

• Targeted therapies matched to specific oncogenic drivers improve survival and quality of life in lung adenocarcinoma patients 2, 5
• Patients with EGFR mutations treated with TKIs and those with ALK fusions treated with alectinib show significantly better outcomes compared to chemotherapy 5
• The percentage of patients who can benefit from targeted therapy has increased by 88% in recent years, highlighting the importance of comprehensive molecular profiling 5

By following this approach, clinicians can maximize the detection of actionable genetic alterations and ensure patients receive the most appropriate targeted therapy, ultimately improving morbidity, mortality, and quality of life outcomes.