Thyroid Cancer

Clinical Overview

Thyroid cancer comprises three major subtypes with fundamentally different biology and ctDNA detection patterns. Differentiated thyroid cancer (DTC: papillary and follicular) accounts for 90% of cases with excellent prognosis but low ctDNA shedding, where thyroglobulin remains the superior monitoring biomarker. Medullary thyroid cancer (MTC) accounts for 3-5% of cases, where calcitonin remains the primary monitoring tool. Anaplastic thyroid cancer (ATC) represents <2% of cases but demonstrates the highest ctDNA detection rates (82-93% concordance) and poorest prognosis. Molecular profiling guides precision therapy across subtypes, with RET alterations, BRAF V600E, and NTRK fusions representing key actionable targets with proven therapeutic benefit.

                    Key Clinical Points
                    DTC (papillary, follicular): Low ctDNA detection (<50% primary disease); thyroglobulin superior for monitoring
MTC (medullary): Low ctDNA detection (32% for RET mutations); calcitonin superior for monitoring
ATC (anaplastic): High ctDNA detection (82-93% concordance); aggressive disease requiring rapid genotyping
ctDNA role in DTC/MTC: Adjunct only when traditional markers interfere (TgAb in 25% DTC patients)
Actionable targets: RET alterations (selpercatinib, pralsetinib), BRAF V600E (dabrafenib + trametinib), NTRK fusions (larotrectinib)

                

Differentiated Thyroid Cancer (DTC): Papillary and Follicular

ctDNA Detection Limitations

DTC ctDNA Performance:

Detection rate: <50% in primary disease
BRAF V600E plasma detection: 31% (vs 100% in tissue)
Clinical context: Low tumor burden and well-differentiated histology limit ctDNA shedding
Standard of care: Thyroglobulin (Tg) remains the gold standard monitoring biomarker
ctDNA utility: Adjunct testing only when thyroglobulin antibodies (TgAb) interfere (25% of patients)

Clinical Interpretation: Well-differentiated thyroid cancers shed minimal ctDNA due to low proliferation rates and small tumor volumes at diagnosis. Thyroglobulin monitoring provides superior sensitivity and specificity for recurrence detection. ctDNA testing should be reserved for the subset of patients with TgAb interference where thyroglobulin is unreliable.

Genotyping for DTC: BRAF V600E and RET Fusions

                    BRAF V600E in Papillary Thyroid Cancer
                    Prevalence: 60% of papillary thyroid cancer
Tissue detection: 100% sensitivity (gold standard)
Plasma detection: 31% sensitivity (insufficient for clinical use)
Clinical recommendation: Tissue biopsy required for reliable BRAF status determination
Therapeutic options: Dabrafenib + trametinib for advanced disease (see ATC section for efficacy data)

                

                    RET Fusions in Differentiated Thyroid Cancer
                    Prevalence: ~25% of DTC in adults
Target therapy: Selpercatinib (RET-selective inhibitor)
Treatment-naive efficacy: ORR 73%
Previously treated efficacy: ORR 69%
Durability: Strong 5-year PFS and OS data
Clinical significance: First-line therapy option for RET fusion-positive advanced DTC

                

NTRK Fusions: Rare but Highly Actionable

Larotrectinib for NTRK Fusion-Positive Thyroid Cancer:

Overall response rate: 75%
Prevalence: Rare (<5% of thyroid cancers)
Clinical utility: Tissue NGS profiling identifies these rare actionable fusions
Target population: Advanced/metastatic disease with NTRK1/2/3 gene fusions

Medullary Thyroid Cancer (MTC)

ctDNA Detection and Monitoring

MTC ctDNA Performance:

RET mutation plasma detection: 32%
Clinical context: Low ctDNA shedding limits utility for routine monitoring
Standard of care: Calcitonin remains the gold standard monitoring biomarker
ctDNA role: Adjunct genotyping for therapy selection, not routine monitoring

RET Alterations: Precision Therapy in MTC

Selpercatinib in Advanced MTC (LIBRETTO-531 Trial)

First-Line Therapy for RET-Mutant MTC:

Trial design: Randomized, Phase III trial in advanced RET-mutant MTC
Comparator: Selpercatinib vs standard of care (cabozantinib or vandetanib)
Primary endpoint: Progression-free survival
Median PFS: Not reached with selpercatinib vs 16.8 months with standard therapy
Hazard ratio: HR 0.28 (72% reduction in progression or death risk)
ORR treatment-naive: 73%
ORR pretreated: 69%
Clinical significance: Establishes selpercatinib as preferred first-line therapy for advanced RET-mutant MTC

                    Pralsetinib: Alternative RET-Selective Inhibitor
                    Mechanism: RET-selective tyrosine kinase inhibitor
Clinical utility: Alternative to selpercatinib for RET-altered MTC
Target population: Advanced RET-mutant or RET fusion-positive MTC

                

Clinical Recommendation: All advanced MTC patients should undergo RET mutation testing (tissue or ctDNA). RET-mutant disease should receive selpercatinib first-line based on LIBRETTO-531 data showing superior PFS compared to multikinase inhibitors. Calcitonin remains the primary monitoring biomarker; ctDNA is supplementary.

Anaplastic Thyroid Cancer (ATC)

ctDNA Detection: Highest Concordance in Thyroid Cancer

ATC ctDNA Performance:

Plasma-tissue concordance: 82-93%
BRAF V600E sensitivity: 85-88% in plasma
Clinical context: Aggressive histology with high tumor burden enables robust ctDNA shedding
Clinical utility: Rapid genotyping via plasma when tissue unavailable or insufficient
Timing advantage: Plasma turnaround faster than tissue in time-sensitive ATC cases

Clinical Rationale: Anaplastic thyroid cancer represents a clinical emergency with median survival measured in months. The high ctDNA concordance (82-93%) enables rapid genotyping to identify BRAF V600E mutations for targeted therapy initiation. When tissue is unavailable or insufficient, plasma genotyping provides actionable results to guide urgent treatment decisions.

BRAF V600E: Dabrafenib + Trametinib in ATC

BRAF/MEK Inhibition in BRAF V600E-Mutant ATC

Clinical Evidence:

BRAF V600E prevalence in ATC: 10-50%
Regimen: Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor)
Overall response rate: 56%
Median overall survival: 14.5 months
Historical comparison: Median OS <6 months with chemotherapy
Clinical significance: >2-fold improvement in survival compared to historical controls
Treatment approach: First-line therapy for BRAF V600E-mutant ATC

Clinical Interpretation: Dabrafenib + trametinib represents a major advance in ATC treatment, improving median OS from <6 months (historical chemotherapy) to 14.5 months. The 56% ORR demonstrates meaningful disease control in this highly aggressive malignancy. All ATC patients require urgent BRAF V600E testing (tissue or ctDNA) to identify candidates for this life-extending therapy.

Genotyping Urgency in ATC

                    Rapid Molecular Profiling for ATC
                    BRAF V600E: 10-50% prevalence; dabrafenib + trametinib (ORR 56%, OS 14.5 months)
RET alterations: Selpercatinib or pralsetinib
NTRK fusions: Larotrectinib (ORR 75%)
Clinical imperative: Median survival <6 months without targeted therapy; genotyping delay reduces treatment window
Testing strategy: Tissue NGS preferred; plasma ctDNA if tissue unavailable (82-93% concordance)

                

Genotyping Clinical Utility: Subtype-Specific Considerations

Alteration	Subtype	Prevalence	Targeted Therapy	Efficacy Data
BRAF V600E	PTC (DTC)	60%	Dabrafenib + trametinib	Advanced disease; efficacy data from ATC
BRAF V600E	ATC	10-50%	Dabrafenib + trametinib	ORR 56%, median OS 14.5 months (vs <6 months historic)
RET fusions	DTC	~25%	Selpercatinib, pralsetinib	ORR 73% (naive), 69% (pretreated); durable 5-year PFS/OS
RET mutations	MTC	Majority (sporadic + hereditary)	Selpercatinib, pralsetinib	LIBRETTO-531: PFS not reached vs 16.8 months (HR 0.28)
NTRK fusions	All subtypes	<5%	Larotrectinib	ORR 75%

Testing Recommendations by Subtype:

DTC: Tissue NGS at diagnosis or recurrence; BRAF and RET testing minimum
MTC: Tissue or germline RET testing mandatory; plasma ctDNA if tissue unavailable
ATC: Urgent tissue NGS preferred; plasma ctDNA acceptable (82-93% concordance) when tissue unavailable
All subtypes: NTRK fusion testing for rare actionable targets (ORR 75% with larotrectinib)

Clinical Summary

                    Evidence-Based Recommendations
                    DTC monitoring: Thyroglobulin remains gold standard; ctDNA adjunct only with TgAb interference (25% patients)
MTC monitoring: Calcitonin remains gold standard; ctDNA for genotyping, not surveillance
ATC genotyping: Urgent testing via tissue NGS or plasma ctDNA (82-93% concordance); BRAF V600E critical for dabrafenib + trametinib eligibility
RET alterations: Selpercatinib first-line for RET-mutant MTC (LIBRETTO-531: HR 0.28); RET fusions in DTC (ORR 73% naive, 69% pretreated)
BRAF V600E in ATC: Dabrafenib + trametinib (ORR 56%, median OS 14.5 months vs <6 months historic)
NTRK fusions: Larotrectinib (ORR 75%) for rare fusion-positive cases
Testing hierarchy: Tissue NGS preferred for DTC/MTC; plasma ctDNA acceptable for urgent ATC genotyping when tissue unavailable

                

Bottom Line: Thyroid cancer ctDNA utility varies dramatically by subtype. Differentiated (DTC) and medullary (MTC) cancers exhibit low ctDNA shedding, with thyroglobulin and calcitonin remaining superior for routine monitoring; ctDNA serves as an adjunct only when traditional markers are unreliable or for genotyping to guide therapy selection. Anaplastic thyroid cancer (ATC) demonstrates high ctDNA concordance (82-93%), enabling rapid plasma genotyping in this clinical emergency. Molecular profiling identifies critical actionable targets: RET alterations (selpercatinib with HR 0.28 in LIBRETTO-531 for MTC; ORR 73% naive, 69% pretreated in DTC), BRAF V600E (dabrafenib + trametinib with ORR 56% and OS 14.5 months in ATC), and NTRK fusions (larotrectinib ORR 75%). Tissue biopsy remains the gold standard for comprehensive molecular characterization in all subtypes.

Clinical Overview

Key Clinical Points