FDA-Approved Liquid Biopsy Tools for Clinical Use
The FDA has approved several liquid biopsy assays for clinical use in oncology, starting with the cobas™ EGFR mutation test in 2016 for non-small cell lung cancer (NSCLC), followed by additional single-gene and multigene panel assays as companion diagnostics for targeted therapies. 1, 2
Currently Approved Assays
Single-Gene Tests
- cobas™ EGFR mutation test v2: FDA-approved companion diagnostic for detecting EGFR-activating mutations in plasma cell-free DNA from NSCLC patients, used to guide EGFR-tyrosine kinase inhibitor (TKI) therapy selection 3, 1
- This test demonstrates superior sensitivity for detecting EGFR exon 20 p.T790M resistance mutations compared to next-generation sequencing (NGS) cfDNA panels 4
Multigene Panel Assays
- Multiple multigene panel assays have been FDA-approved more recently as companion diagnostics matched to specific molecularly targeted therapies 2
- These broader panels enable detection of various actionable mutations including KRAS G12V in colorectal cancer and BRAF V600E/V600K in melanoma 3
Clinical Applications by Category
Diagnosis and Treatment Selection
- Primary use: Identifying patients eligible for targeted therapies when tissue biopsy is unavailable, failed previous molecular analysis, or patient is clinically ineligible for biopsy procedures 5
- Enables non-invasive predictive biomarker testing for treatment optimization 5
- Particularly valuable for interrogating difficult-to-biopsy tumors 6
Treatment Monitoring and Resistance Detection
- Serial monitoring: Detects treatment-selected resistance mutations such as EGFR T790M in NSCLC 3
- Can identify resistance mutations prior to radiographic disease progression on CT imaging 4
- Allows longitudinal monitoring of tumor genomes to complement tissue biopsies 3
Prognostic Applications
- Tumor burden assessment: Copy number instability (CNI) scores derived from chromosomal aberration patterns in cell-free DNA can predict therapeutic response to chemotherapy/immunotherapy 3
- Changes in CNI score serve as early predictors of therapeutic response across multiple cancer types 3
- In multivariable models, CNI score was superior to clinical parameters for predicting overall survival in head and neck cancer 3
Key Limitations and Caveats
Technical Challenges
- Sensitivity limitations: Detection of very early-stage tumors is difficult due to insufficient mutant DNA fraction of ≤0.01% 3
- Clonal hematopoiesis: cfDNA assessment can be confounded by clonal hematopoiesis of indeterminate potential, especially in elderly patients 6
Reporting Complexity
- ctDNA interpretation and reporting are more complex than conventional tissue-based NGS, requiring specific guidelines for optimal communication between diagnostic laboratories and oncology teams 5
- Expert manual curation remains necessary despite automation of most analytical steps 7
Emerging Applications Under Investigation
Post-Surgical Monitoring
- ctDNA relapse detection: The next frontier involves monitoring ctDNA after curative-intent surgery to predict prognosis and detect disease relapse earlier than conventional imaging 1, 2
- Clinical utility is currently under assessment in several prospective clinical trials 1
Immunotherapy Biomarkers
- Blood tumor mutation burden (bTMB): Promising approach for predicting immune checkpoint inhibitor efficacy, though still under clinical validation 1
Beyond Blood
- Future research is expanding to other body fluids including ascites, pleural effusions, urine, and cerebrospinal fluid 6
Important note: While FDA-approved liquid biopsy tests are validated for specific clinical indications, they cannot replace physician judgment—clinical decision-making must integrate NGS results with other diagnostic tests, patient medical history, and individual preferences, ideally with multidisciplinary team support 7