Evidence-Based Liquid Biopsy Knowledge
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Liver Cancer (Hepatocellular Carcinoma)

ctDNA MRD Monitoring Shows Strong Prognostic Value; Limited Genotyping Utility in Advanced Disease

Clinical Overview

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, typically arising in patients with chronic liver disease from hepatitis B/C, alcohol, or NASH. The disease presents unique challenges: most patients have underlying cirrhosis with liver dysfunction, and recurrence rates approach 70% within 5 years after curative-intent resection or ablation.

ctDNA testing in HCC has two distinct applications with markedly different clinical utility. MRD detection after curative-intent treatment demonstrates strong prognostic value (HR 3.7-15 for recurrence), with detection 2-6 months before imaging and performance superior to AFP. In contrast, genotyping for treatment selection has limited utility compared to other solid tumors, as HCC has few actionable mutations and most systemic therapy decisions are based on clinical factors rather than genomic alterations.

ctDNA Clinical Utility in HCC

  • MRD monitoring (established): Strong prognostic value for recurrence risk (HR 3.7-15), superior to AFP (ctDNA HR 8.2 vs AFP HR 2.1)
  • Early detection: ctDNA detected recurrence 2-6 months before imaging in multiple studies
  • Stage-dependent sensitivity: 70-93% in advanced disease; lower sensitivity in early-stage HCC
  • Genotyping (limited utility): Few targetable mutations; most treatment decisions based on clinical criteria
  • AFP remains standard: ctDNA does not replace AFP monitoring; AFP is cheaper, easier, and well-established

ctDNA Testing Methodology

HCC ctDNA testing employs both tumor-informed and tumor-agnostic approaches, depending on the clinical application.

Tumor-Informed (Baseline-Based) Approach

Method: Baseline sample (tissue biopsy or baseline blood draw) identifies patient-specific mutations, which are then tracked at subsequent MRD monitoring timepoints.

Clinical Use in HCC:

  • Primary application: Postoperative MRD monitoring after resection/ablation
  • Approach: Baseline tumor profiling identifies somatic mutations, which are tracked in serial blood draws post-treatment
  • Advantage: Higher sensitivity for MRD detection by tracking known patient-specific variants
  • Clinical context: Best suited for patients with curative-intent treatment where baseline tumor tissue is available

Tumor-Agnostic (No Baseline) Approach

Method: Testing performed directly at MRD timepoint without prior baseline profiling, using fixed gene panels to detect common cancer mutations.

Clinical Use in HCC:

  • Primary application: Treatment monitoring in advanced disease; screening scenarios
  • Approach: Fixed panels targeting common HCC mutations (TP53, CTNNB1, TERT promoter)
  • Limitation: Lower sensitivity than tumor-informed MRD monitoring
  • Clinical context: Useful when baseline tissue unavailable or for genotyping in advanced disease
  • Note: Biopsy often avoided in HCC due to cirrhosis and coagulopathy risk

Technical Considerations: Both approaches utilize next-generation sequencing with varying panel sizes. Tumor-informed approaches typically provide higher MRD detection sensitivity by tracking known patient-specific variants, while tumor-agnostic testing offers convenience but may miss mutations not included in the fixed panel.

MRD Detection: Clinical Utility and Performance vs AFP

Clinical Context: After curative-intent treatment (resection, ablation), distinguishing true cure from microscopic residual disease is challenging. Both ctDNA and AFP (alpha-fetoprotein) can detect recurrence, but multiple studies demonstrate ctDNA provides superior prognostic stratification.

ctDNA vs AFP: Comparative Performance

Parameter ctDNA MRD AFP Clinical Interpretation
Hazard Ratio for Recurrence HR 3.7-15 (varies by study) HR 2.1 (when elevated) ctDNA provides stronger prognostic stratification
Direct Comparison Study HR 8.2 (95% CI 3.2-21.4) HR 2.1 (95% CI 0.8-5.4) 4-fold stronger risk prediction with ctDNA (Cai et al. 2019)
Sensitivity (Advanced Disease) 70-93% 50-60% ctDNA detects more recurrences
Sensitivity (Early Stage) Lower (30-60%) Lower (20-40%) Both methods limited in early disease
Lead Time Before Imaging 2-6 months 1-3 months Earlier detection window with ctDNA
Specificity High (tumor-specific mutations) Moderate (elevated in cirrhosis, hepatitis) ctDNA more specific for cancer vs inflammation
Cost Higher Lower AFP remains more accessible
Clinical Adoption Emerging Standard of care AFP established; ctDNA complementary

Key MRD Detection Data

Cai et al. (Clin Cancer Res 2019) - Direct ctDNA vs AFP Comparison:

  • ctDNA recurrence prediction: HR 8.2 (95% CI 3.2-21.4, p<0.001)
  • AFP recurrence prediction: HR 2.1 (95% CI 0.8-5.4, p=0.13, not significant)
  • Clinical interpretation: ctDNA 4-fold stronger predictor than AFP in same patient cohort
  • Detection timing: ctDNA identified recurrence 3-6 months before imaging

Liao et al. (Clin Chem 2016):

  • Overall survival: HR 2.99 for death with detectable postoperative ctDNA
  • Recurrence-free survival: HR 4.48 (p<0.001)
  • Lead time: ctDNA detected recurrence 2-4 months before imaging

Ahn et al. (Cancer Med 2020):

  • Recurrence prediction: HR 15.0 for recurrence with postoperative ctDNA positivity
  • Sensitivity: 93% in advanced disease; 50% in early-stage disease
  • Lead time: Median 5.5 months before radiographic recurrence

Xiong et al. (Int J Cancer 2023):

  • Recurrence-free survival: HR 3.7 (95% CI 2.1-6.4, p<0.001)
  • Overall survival: HR 4.1 (95% CI 2.0-8.2, p<0.001)
  • Clinical utility: ctDNA+ patients had 4-fold higher recurrence risk

Clinical Interpretation: When to Use ctDNA vs AFP

AFP Remains Standard Biomarker:

  • Lower cost and simpler methodology (protein assay vs genomic sequencing)
  • Decades of clinical validation and established monitoring protocols
  • Widely available at all medical centers
  • Useful for initial screening and monitoring trends over time

ctDNA Provides Complementary Value:

  • Superior prognostic stratification (HR 3.7-15 vs HR 2.1 for AFP)
  • Higher sensitivity, particularly in advanced disease (70-93% vs 50-60%)
  • More specific for cancer (not elevated by cirrhosis/hepatitis like AFP)
  • Longer lead time before imaging detection (2-6 months vs 1-3 months)
  • Useful when AFP is non-elevated at baseline (30-40% of HCC cases)

Practical Approach: ctDNA does not replace AFP but provides complementary information. Many clinicians use AFP as first-line monitoring (cost-effective, established) and consider ctDNA for:

  • Patients with non-elevated baseline AFP
  • High-risk patients requiring maximal surveillance sensitivity
  • Clinical trial enrollment or adjuvant therapy decision-making
  • Ambiguous AFP elevation (cirrhosis vs recurrence)

Clinical Significance: While ctDNA demonstrates superior prognostic performance, no randomized trials have proven that acting on MRD information improves outcomes in HCC. Current clinical utility is primarily for risk stratification: identifying high-risk ctDNA+ patients for intensive surveillance, enrollment in adjuvant therapy trials, or consideration of closer monitoring intervals. AFP remains the standard biomarker due to cost and accessibility, but ctDNA provides complementary value, particularly in AFP-negative disease.

References: Cai et al. Clin Cancer Res 2019, Liao et al. Clin Chem 2016, Ahn et al. Cancer Med 2020, Xiong et al. Int J Cancer 2023

Genotyping for Treatment Selection: Limited Clinical Utility

Critical Context: Unlike many solid tumors (e.g., lung, colorectal, breast) where genomic alterations directly guide targeted therapy selection, HCC has very few actionable mutations. Most treatment decisions in advanced HCC are based on liver function (Child-Pugh score), performance status, and prior treatment lines rather than molecular profiling.

Why Genotyping Has Limited Utility in HCC

  • Few targetable mutations: Unlike EGFR in lung cancer or KRAS in colorectal cancer, HCC lacks common actionable alterations
  • Treatment selection is clinical: First-line therapy (atezolizumab-bevacizumab) used regardless of genomics
  • No approved targeted therapies: Most systemic options (sorafenib, lenvatinib, cabozantinib) are multi-kinase inhibitors used empirically
  • Emerging biomarkers unvalidated: TERT, CTNNB1 show associations but not yet used for treatment decisions

Current Treatment Landscape in Advanced HCC

Treatment Line Standard Options Key Trial Data Genomic Selection?
First-Line Atezolizumab + bevacizumab IMbrave150: OS HR 0.58 (95% CI 0.42-0.79)
PFS HR 0.59 (95% CI 0.47-0.76)		 No - used in all eligible patients
First-Line Alternative Lenvatinib REFLECT: Non-inferior to sorafenib (OS 13.6 vs 12.3 months) No - clinical selection (contraindication to bevacizumab)
First-Line Alternative Sorafenib SHARP: OS 10.7 vs 7.9 months (HR 0.69)
(Former standard, now second-line role)		 No - clinical selection
Second-Line Cabozantinib CELESTIAL: OS 10.2 vs 8.0 months (HR 0.76) No - used after first-line progression
Second-Line Regorafenib RESORCE: OS 10.6 vs 7.8 months (HR 0.63) No - used after sorafenib progression

IMbrave150: Current Standard of Care

Trial Design: Phase 3 randomized trial of atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) vs sorafenib in treatment-naive advanced HCC.

Efficacy Results:

  • Overall survival: 19.2 months vs 13.4 months (HR 0.58, 95% CI 0.42-0.79, p<0.001)
  • Progression-free survival: 6.8 months vs 4.3 months (HR 0.59, 95% CI 0.47-0.76, p<0.001)
  • Objective response rate: 27% vs 12% (p<0.001)
  • Duration of response: 18.1 months vs 14.9 months

Clinical Impact: Atezolizumab-bevacizumab is now standard first-line therapy for unresectable HCC. Treatment selection is based on clinical eligibility (adequate liver function, no contraindication to bevacizumab), not molecular profiling.

Common HCC Mutations: Emerging but Not Actionable

TERT Promoter Mutations (51-61.5% prevalence):

  • Function: Activate telomerase, enabling chromosome stability in cancer cells
  • Association: Emerging data suggests possible association with better immunotherapy response
  • Clinical use: Not currently used for treatment selection; atezolizumab-bevacizumab given regardless of TERT status
  • Limitation: No TERT-targeted therapy available; association with immunotherapy response requires validation

CTNNB1/β-Catenin Mutations (17-34% prevalence):

  • Function: Activate WNT signaling pathway
  • Association: "Immune-excluded" tumor phenotype; potential predictor of poor immunotherapy response
  • Clinical use: Not currently used to exclude patients from immunotherapy
  • Limitation: No WNT-targeted therapy available; negative predictive value unproven
  • Note: Even if CTNNB1 mutated, patients still receive atezolizumab-bevacizumab (no alternative superior option)

TP53 Mutations (32-33% prevalence):

  • Function: Tumor suppressor gene; mutations associated with aggressive biology
  • Association: Generally worse prognosis
  • Clinical use: No treatment implication; no TP53-targeted therapy
  • Limitation: Purely prognostic, not actionable

Contrast with Other Solid Tumors

HCC genotyping has markedly less clinical utility compared to other cancers:

High-Utility Genotyping Examples:

  • Lung adenocarcinoma: EGFR mutations → osimertinib (OS 38.6 vs 31.8 months); ALK rearrangements → alectinib (5-year OS 62.5%)
  • Colorectal cancer: RAS/BRAF wild-type → anti-EGFR therapy (cetuximab, panitumumab); BRAF V600E → encorafenib-cetuximab (OS 15.3 vs 9.3 months)
  • Breast cancer: HER2 amplification → trastuzumab-deruxtecan (PFS 28.8 vs 6.8 months); PIK3CA mutations → alpelisib
  • Melanoma: BRAF V600E → dabrafenib-trametinib (OS HR 0.70 vs chemotherapy)

HCC Reality:

  • No genomic alteration that directs specific targeted therapy selection
  • First-line treatment (atezolizumab-bevacizumab) used regardless of molecular profile
  • Alternative first-line (lenvatinib, sorafenib) selected by clinical factors, not genomics
  • Second-line options (cabozantinib, regorafenib) selected by prior treatment and clinical factors
  • Emerging biomarkers (TERT, CTNNB1) show associations but lack validation and actionable therapy

Clinical Bottom Line: Unlike many solid tumors where genotyping directly guides targeted therapy selection, HCC treatment decisions are predominantly clinical (liver function, performance status, prior therapies). ctDNA genotyping in advanced HCC provides limited actionable information, as most patients receive the same first-line therapy (atezolizumab-bevacizumab) regardless of molecular profile. Emerging biomarkers like TERT and CTNNB1 may eventually inform treatment selection, but currently lack validation and do not change clinical management.

References: Finn et al. N Engl J Med 2020, Kudo et al. Lancet 2018, Abou-Alfa et al. N Engl J Med 2018, Bruix et al. Lancet Oncol 2017, Schulze et al. Nat Genet 2015

Clinical Summary

ctDNA testing in hepatocellular carcinoma demonstrates established prognostic utility for MRD detection after curative-intent treatment, but has limited utility for genotyping and treatment selection in advanced disease.

Clinical Recommendations by Setting

Curative-Intent Treatment (MRD Monitoring):

  • Prognostic value: Strong risk stratification (HR 3.7-15 for recurrence with detectable postoperative ctDNA)
  • Superior to AFP: ctDNA HR 8.2 vs AFP HR 2.1 in direct comparison; longer lead time (2-6 vs 1-3 months)
  • Sensitivity: 70-93% in advanced disease; lower (30-60%) in early-stage HCC
  • Best application: AFP-negative disease, high-risk patients, clinical trial enrollment
  • Limitation: AFP remains standard due to cost and accessibility; no interventional trial proving improved outcomes
  • Practical use: Complementary to AFP, not replacement; use for risk stratification and surveillance intensity decisions

Advanced Disease (Genotyping for Treatment Selection):

  • Clinical reality: Very limited utility compared to other solid tumors
  • First-line standard: Atezolizumab-bevacizumab (IMbrave150: OS HR 0.58, PFS HR 0.59) used in all eligible patients regardless of genomics
  • Treatment selection: Based on clinical factors (liver function, performance status, contraindications), not molecular profile
  • Common mutations unactionable: TERT (51-61.5%), CTNNB1 (17-34%), TP53 (32-33%) lack targeted therapies
  • Emerging biomarkers: TERT/CTNNB1 associations with immunotherapy response require validation
  • Recommendation: Do not routinely genotype for treatment selection; reserve for biomarker-selected clinical trials

Comparison to Other Cancers:

  • Lung cancer: EGFR, ALK, ROS1, BRAF → direct therapy selection with dramatic OS benefit
  • Colorectal cancer: RAS/BRAF → anti-EGFR selection; BRAF V600E → targeted therapy
  • HCC reality: No genomic alteration directs specific therapy; treatment predominantly clinical
Application Evidence Level Clinical Utility Current Recommendation
MRD after resection/ablation Strong prognostic (HR 3.7-15) Risk stratification; superior to AFP Consider in AFP-negative disease, high-risk patients, trials
Early detection before imaging Demonstrated (2-6 month lead time) Earlier recurrence detection Complementary to imaging; does not replace surveillance
Genotyping for treatment selection Limited/emerging Very low - few actionable mutations Not routinely recommended; use in biomarker trials only
Treatment monitoring (advanced) Emerging Moderate - complements imaging/AFP Research setting; imaging remains standard

Bottom Line: ctDNA in HCC has two distinct clinical utilities. MRD monitoring after curative treatment demonstrates strong prognostic value (HR 3.7-15) with performance superior to AFP, though AFP remains standard due to cost and accessibility. ctDNA provides complementary value, particularly in AFP-negative disease. Genotyping for treatment selection in advanced disease has very limited utility compared to other solid tumors, as HCC has few actionable mutations and treatment decisions are predominantly clinical rather than genomically driven. Unlike lung or colorectal cancer where molecular profiling directly guides therapy, most HCC patients receive atezolizumab-bevacizumab first-line regardless of genomic alterations.

References

  1. Cai Z et al. Comprehensive liquid profiling of circulating tumor DNA and protein biomarkers in long-term follow-up patients with hepatocellular carcinoma. Clin Cancer Res 2019;25:5284-5294.
  2. Liao W et al. Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma. Clin Chem 2016;62:1377-1386.
  3. Ahn JC et al. Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Cancer Med 2020;9:2408-2419.
  4. Xiong Y et al. Circulating tumor DNA as a prognostic and predictive biomarker in hepatocellular carcinoma. Int J Cancer 2023;152:2470-2481.
  5. Finn RS et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
  6. Kudo M et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-1173.
  7. Abou-Alfa GK et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
  8. Bruix J et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
  9. Schulze K et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505-511.

Evidence summary as of January 2026 | Document Version: 2.0