Liqomics Evidence-Based Liquid Biopsy Knowledge
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Sarcoma

Circulating Tumor DNA in Heterogeneous Mesenchymal Malignancies

Clinical Overview

Sarcomas represent a heterogeneous group of over 70 histologic subtypes arising from mesenchymal tissues, including bone, soft tissue, and visceral organs. This extreme heterogeneity profoundly impacts ctDNA testing performance, with detection rates and clinical utility varying substantially across subtypes. Unlike epithelial malignancies, many sarcomas are "low-shedder" tumor types, presenting unique challenges for liquid biopsy applications.

Clinical Impact: ctDNA testing in sarcoma serves two distinct clinical purposes: minimal residual disease (MRD) detection for prognostication and surveillance, and comprehensive genotyping for identification of actionable therapeutic targets. Performance varies dramatically by subtype, with GIST and dedifferentiated liposarcoma demonstrating superior detection compared to leiomyosarcoma and other subtypes.

Key Subtype-Specific Characteristics:

  • GIST: 70-80% harbor KIT mutations (exons 11/9); favorable ctDNA detection rates
  • Liposarcoma: MDM2 amplification; higher ctDNA shedding, particularly dedifferentiated subtype
  • Leiomyosarcoma: TP53, RB1 mutations; lower ctDNA detection rates; limited targeted options
  • Synovial sarcoma: SS18-SSX fusion; investigational targeted therapies
  • NTRK fusion-positive sarcomas: Rare but highly actionable with TRK inhibitors

Understanding ctDNA Testing in Sarcoma

What is Circulating Tumor DNA (ctDNA)?

Circulating tumor DNA (ctDNA) represents fragments of tumor-derived DNA that are released into the bloodstream when cancer cells die. These DNA fragments carry the same genetic alterations present in the tumor, making them detectable through a simple blood draw rather than invasive tissue biopsy.

Challenges Unique to Sarcoma ctDNA Testing

Low-Shedder Tumor Biology:

  • Lower ctDNA release: Many sarcomas shed less DNA into circulation compared to carcinomas
  • Tumor location impact: Retroperitoneal and intramuscular tumors may have limited vascular access
  • Slow growth rates: Well-differentiated subtypes release minimal ctDNA
  • Histologic diversity: >70 subtypes with distinct molecular profiles require subtype-specific panels

Testing Approaches: Tumor-Informed vs Tumor-Agnostic

Tumor-Informed (Baseline-Based) Approach

How it works: Uses a baseline sample (tissue biopsy OR baseline plasma/blood) to identify the patient's tumor mutations, then tracks those specific mutations at MRD timepoints

Performance in Sarcoma:

  • MRD sensitivity: 40-78% (varies by subtype)
  • Higher sensitivity in GIST and dedifferentiated liposarcoma (60-78%)
  • Lower sensitivity in leiomyosarcoma (40-50%)
  • Lead time: 2-4 months before imaging-detected recurrence

Best used for:

  • Post-surgical MRD detection in high-grade sarcomas
  • Monitoring during adjuvant/neoadjuvant therapy
  • Early relapse detection in high-risk subtypes

Requirements: Baseline sample (tissue from surgery or blood sample) for initial mutation identification

Tumor-Agnostic (No Baseline) Approach

How it works: Tests directly at timepoint without prior baseline profiling, using panels covering actionable sarcoma mutations

Advantages:

  • No baseline sample required
  • Faster turnaround (5-7 days vs 2-3 weeks)
  • Can detect emerging resistance mutations
  • Identifies actionable targets (KIT, NTRK, PDGFRA)

Best used for:

  • Advanced/metastatic disease genotyping
  • Treatment selection based on actionable mutations
  • Monitoring for resistance during targeted therapy
  • Cases where baseline tissue profiling was not performed

Limitations: Lower sensitivity for MRD; may miss low-frequency mutations

Clinical Decision Points for Sarcoma Subtypes

When to Use Each Approach

Clinical Scenario Recommended Approach Rationale
Post-surgical MRD (high-grade sarcoma) Tumor-informed Maximum sensitivity needed; tracks patient-specific mutations
GIST genotyping for treatment selection Either approach KIT mutations detectable with or without baseline
NTRK fusion screening Tumor-agnostic (RNA-based) Rare fusions require comprehensive fusion panels
Imatinib resistance monitoring in GIST Either approach Secondary KIT mutations can emerge during treatment
Liposarcoma MDM2 amplification Either approach Copy number alterations detectable by both methods

Minimal Residual Disease Detection: Clinical Utility by Subtype

Prognostic Value Varies with Sarcoma Type

Overview: MRD detection in sarcoma demonstrates subtype-specific performance, with GIST and dedifferentiated liposarcoma showing superior detection rates compared to leiomyosarcoma and other subtypes. The heterogeneity of sarcoma biology fundamentally impacts ctDNA shedding and detection sensitivity.

MRD Detection Performance by Subtype

GIST (Gastrointestinal Stromal Tumor):

  • MRD sensitivity: 60-78%
  • Lead time: 2-4 months before imaging recurrence
  • Prognostic value: Strong correlation with recurrence risk
  • Hazard ratio: 4.8-8.0 for recurrence with ctDNA positivity
  • Clinical context: Highest detection rates among sarcoma subtypes

Dedifferentiated Liposarcoma:

  • MRD sensitivity: 65-75%
  • Lead time: 2-3 months before imaging recurrence
  • Hazard ratio: 6.5-12.0 for recurrence with ctDNA positivity
  • Key marker: MDM2 amplification facilitates detection
  • Clinical utility: Favorable detection due to high tumor burden

Leiomyosarcoma:

  • MRD sensitivity: 40-50% (lower than other subtypes)
  • Lead time: 1-3 months before imaging (when detected)
  • Hazard ratio: 8.0-18.0 for recurrence with ctDNA positivity
  • Challenges: Lower ctDNA shedding; variable molecular profiles
  • Clinical limitation: Frequent false negatives limit utility

Synovial Sarcoma:

  • MRD sensitivity: 50-65%
  • Molecular marker: SS18-SSX fusion transcript
  • Detection method: RNA-based testing preferred
  • Clinical utility: Moderate detection rates; fusion-specific monitoring

Undifferentiated Pleomorphic Sarcoma:

  • MRD sensitivity: 45-60%
  • Challenge: Heterogeneous molecular profiles without recurrent driver mutations
  • Approach: Tumor-informed testing essential due to patient-specific mutations

Clinical Interpretation Across Subtypes

Key Findings:

  • Highest utility: GIST and dedifferentiated liposarcoma (60-78% sensitivity)
  • Moderate utility: Synovial sarcoma, undifferentiated pleomorphic sarcoma (50-65%)
  • Limited utility: Leiomyosarcoma (40-50% sensitivity)
  • Universal limitation: Lower sensitivity compared to epithelial tumors (70-90%)
  • Lead time advantage: 2-4 months when ctDNA is detectable
  • Hazard ratios: 4.8-18.0 depending on subtype (strong prognostic value when detected)

Clinical Significance: While MRD detection in sarcoma demonstrates strong prognostic value when ctDNA is detected, the lower sensitivity compared to carcinomas means negative results cannot exclude residual disease. Tissue biopsy remains essential for definitive diagnosis, and ctDNA should be integrated with imaging and clinical assessment rather than used as a standalone test.

Genotyping for Targeted Therapy Selection

Subtype-Specific Molecular Profiling

Overview: Sarcoma genotyping via ctDNA enables identification of actionable mutations and selection of targeted therapies. Unlike MRD detection, genotyping focuses on treatment-guiding alterations rather than prognostication.

GIST: KIT and PDGFRA Mutations

KIT Exon 11 Mutations (60-70% of GIST):

  • First-line therapy: Imatinib
  • Overall response rate: 54-83%
  • Median progression-free survival: 18-24 months
  • ctDNA detection: >90% sensitivity for KIT mutations
  • Clinical utility: Confirms diagnosis and guides initial therapy

KIT Exon 9 Mutations (10-15% of GIST):

  • First-line therapy: Imatinib (higher dose 400mg BID)
  • Overall response rate: 48-67% (dose-dependent)
  • Clinical implication: Exon 9 mutations predict benefit from dose escalation
  • ctDNA utility: Non-invasive mutation detection guides dosing strategy

PDGFRA D842V Mutation (5-10% of GIST):

  • Clinical challenge: Primary resistance to imatinib, sunitinib, regorafenib
  • Targeted therapy: Avapritinib
  • Overall response rate: 84% (NAVIGATOR trial)
  • Median progression-free survival: 24 months
  • ctDNA detection: Identifies imatinib-resistant genotype pre-treatment
  • Clinical impact: Avoids futile imatinib therapy and selects appropriate first-line treatment

Secondary KIT Mutations (Resistance Monitoring):

  • Context: Emerge in 30-50% of GIST during imatinib therapy
  • Common resistance mutations: KIT exons 13, 14, 17, 18
  • Clinical action: Switch to sunitinib or regorafenib based on mutation pattern
  • ctDNA monitoring: Serial testing every 3-4 months during therapy
  • Lead time advantage: Detects resistance 1-3 months before imaging progression

Liposarcoma: MDM2 Amplification and Targeted Approaches

MDM2 Amplification (Well-Differentiated/Dedifferentiated Liposarcoma):

  • Prevalence: >95% of dedifferentiated liposarcoma
  • Diagnostic utility: Differentiates from other high-grade sarcomas
  • ctDNA detection: Copy number analysis via liquid biopsy
  • Targeted therapy: MDM2 inhibitors in clinical trials
    • Alrizomadlin: Phase II/III trials ongoing
    • Brigimadlin: Early phase studies
  • Current limitation: No approved MDM2-targeted therapies; trial enrollment recommended
  • Future potential: MDM2 amplification may become actionable biomarker

Leiomyosarcoma: Limited Targeted Options

TP53 and RB1 Mutations (40-60% of LMS):

  • Clinical challenge: Tumor suppressor mutations are not directly targetable
  • Prognostic value: TP53 mutation associated with worse outcomes
  • Current approach: Cytotoxic chemotherapy (doxorubicin, gemcitabine/docetaxel)
  • Investigational strategies:
    • CDK4/6 inhibitors (for RB1 wild-type)
    • Synthetic lethality approaches targeting TP53 pathway
  • ctDNA utility: Limited therapeutic actionability; primarily prognostic

Synovial Sarcoma: SS18-SSX Fusions

SS18-SSX Fusion Transcript (>95% of Synovial Sarcoma):

  • Diagnostic utility: Pathognomonic fusion confirms diagnosis
  • Detection method: RNA-based liquid biopsy required for fusion detection
  • ctDNA sensitivity: 50-70% for fusion transcript detection in advanced disease
  • Targeted therapy: Clinical trials investigating:
    • EZH2 inhibitors (tazemetostat)
    • HDAC inhibitors
    • SS18-SSX peptide vaccines
  • Current limitation: No approved fusion-targeted therapies; standard chemotherapy remains first-line

NTRK Fusion-Positive Sarcomas: Highly Actionable Rare Alteration

NTRK1/2/3 Fusions (1-5% of Sarcomas, Varies by Subtype):

  • Enriched subtypes: Infantile fibrosarcoma (>90%), congenital mesoblastic nephroma, spindle cell sarcoma
  • Rare in: Adult soft tissue sarcomas (<1%)
  • Larotrectinib (First-Generation TRK Inhibitor):
    • Overall response rate: 75-79% in sarcomas
    • Median duration of response: Not reached (>80% ongoing at 12 months)
    • Progression-free survival: Median not reached
  • Entrectinib (First-Generation TRK Inhibitor):
    • Overall response rate: 57-63% in sarcomas
    • Median duration of response: 10-21 months
    • CNS activity: Crosses blood-brain barrier
  • ctDNA detection: RNA-based panels required; DNA-based testing misses most fusions
  • Clinical recommendation: Test all sarcomas without known driver mutations, especially pediatric cases

Integrated Genotyping Strategy

Recommended Molecular Profiling Approach:

  1. Initial Diagnosis: Comprehensive tissue profiling (tissue remains gold standard for sarcoma diagnosis)
  2. Advanced/Metastatic Disease: ctDNA genotyping when tissue unavailable or insufficient
    • GIST: KIT, PDGFRA mutation panel
    • Liposarcoma: MDM2 amplification, CDK4 amplification
    • Unknown driver: Comprehensive DNA + RNA panel including NTRK fusions
  3. Treatment Monitoring: Serial ctDNA for resistance mutation detection (especially GIST on TKI therapy)
  4. Clinical Trial Enrollment: Genotyping identifies patients for biomarker-selected trials

Clinical Implications: Genotyping via ctDNA provides actionable information for GIST (KIT/PDGFRA mutations) and rare NTRK fusion-positive sarcomas, with dramatic treatment responses to targeted therapies. For other subtypes like leiomyosarcoma and synovial sarcoma, targeted options remain limited, though clinical trial enrollment should be considered. Tissue biopsy remains essential for sarcoma diagnosis and comprehensive profiling, with ctDNA serving as a complementary tool when tissue is unavailable or for longitudinal monitoring.

Clinical Summary & Practice Recommendations

Sarcoma ctDNA testing demonstrates highly variable clinical utility dependent on histologic subtype:

  1. Highest Utility - GIST: 60-78% MRD sensitivity; KIT/PDGFRA mutations guide imatinib/avapritinib selection (ORR 54-84%)
  2. Moderate Utility - Dedifferentiated Liposarcoma: 65-75% MRD sensitivity; MDM2 amplification diagnostic
  3. Limited Utility - Leiomyosarcoma: 40-50% MRD sensitivity; no actionable targeted therapies
  4. Critical for NTRK Fusions: Rare (1-5%) but highly actionable with TRK inhibitors (ORR 75-79%)
  5. Low-Shedder Biology: Sarcomas shed less ctDNA than carcinomas; high false-negative rates
  6. Tissue Remains Essential: ctDNA cannot replace biopsy for diagnosis or comprehensive profiling

Evidence-Based Implementation Strategy

Recommended Clinical Pathway by Subtype:

GIST (Highest Evidence):

  • Initial diagnosis: KIT/PDGFRA genotyping (tissue or ctDNA)
  • Treatment selection: Imatinib for KIT exon 11; dose escalation for exon 9; avapritinib for PDGFRA D842V
  • MRD monitoring: Post-surgical ctDNA at 4-8 weeks, then every 3-4 months for 2 years
  • Resistance surveillance: Serial ctDNA every 3 months during TKI therapy for secondary mutations

Dedifferentiated Liposarcoma:

  • Diagnosis confirmation: MDM2 amplification via tissue or ctDNA
  • MRD monitoring: Post-surgical ctDNA every 3-6 months (65-75% sensitivity)
  • Clinical trial screening: MDM2 inhibitor trials for advanced disease

Leiomyosarcoma:

  • Limited role: ctDNA not recommended for routine MRD monitoring (40-50% sensitivity)
  • Consider genotyping only: For clinical trial enrollment in advanced disease
  • Standard surveillance: Imaging remains primary modality

Unknown Driver / Rare Subtypes:

  • Comprehensive profiling: DNA + RNA panel including NTRK, ROS1, ALK fusions
  • Clinical trial matching: Genotyping identifies biomarker-selected trial opportunities

When to Order ctDNA Testing in Sarcoma

Clinical Indication Recommendation Rationale
GIST genotyping for treatment selection Strongly Recommend KIT/PDGFRA mutations guide therapy; high detection rate
NTRK fusion screening (unknown driver) Consider Rare but highly actionable; RNA-based panel required
Post-surgical MRD in GIST or dedifferentiated liposarcoma Consider 60-75% sensitivity; strong prognostic value when detected
Resistance monitoring during GIST TKI therapy Consider Detects secondary KIT mutations 1-3 months before imaging
Leiomyosarcoma MRD monitoring Not Recommended 40-50% sensitivity; imaging surveillance preferred
Low-grade sarcoma surveillance Not Recommended <20% detection rate; clinically unreliable
Primary sarcoma diagnosis Not Appropriate Tissue biopsy mandatory for histologic classification

Clinical Implementation: ctDNA testing in sarcoma requires a nuanced, subtype-specific approach given the extreme heterogeneity of these malignancies. While GIST demonstrates the strongest evidence for both genotyping and MRD detection, other subtypes show more limited sensitivity and actionability. The low-shedder biology of many sarcomas fundamentally limits ctDNA utility compared to epithelial tumors. Tissue biopsy remains the gold standard for diagnosis and comprehensive molecular profiling, with ctDNA serving as a complementary tool for longitudinal monitoring in select subtypes and for genotyping when tissue is unavailable. Negative ctDNA results must be interpreted with extreme caution and cannot exclude recurrence or residual disease in this tumor type.

References

  1. Kang G et al. Detection of circulating tumor DNA in patients with gastrointestinal stromal tumor with peritoneal seeding. Sci Rep 2020;10:21004.
  2. Boonstra PA et al. Prognostic value of circulating tumor DNA in gastrointestinal stromal tumors: A systematic review. Mol Oncol 2021;15:3206-3219.
  3. Bertucci F et al. Genomic characterization of metastatic breast cancers. Nature 2019;569:560-564.
  4. Grünewald TGP et al. Sarcoma treatment in the era of molecular medicine. EMBO Mol Med 2020;12:e11131.
  5. Schöffski P et al. Activity and safety of ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:923-934.
  6. Jones RL et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer 2021;145:132-142.
  7. Drilon A et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739.
  8. Doebele RC et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-282.
  9. Bill KLJ et al. Degree of MDM2 amplification affects clinical outcomes in dedifferentiated liposarcoma. Oncologist 2019;24:989-995.
  10. Gounder MM et al. Alrizomadlin (APG-115) for patients with TP53 wild-type solid tumors and MDM2 amplification: Phase 1 dose escalation and expansion. J Clin Oncol 2023;41(suppl):3003.
  11. Chalmers ZR et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9:34.
  12. Petitprez F et al. Review of prognostic expression markers for osteosarcoma. Expert Rev Mol Diagn 2021;21:201-213.

Evidence summary current through January 2026 | Document Version: 2.0

This educational resource incorporates the latest clinical data for ctDNA testing in sarcoma