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RET Fusion-Positive Thyroid Cancer

RET Fusion‑Positive Thyroid Cancer — Disease Characteristics Research Report

2026-04-05
Falcon MONDO:0005075 Model: Edison Scientific Literature 55 citations

RET Fusion‑Positive Thyroid Cancer — Disease Characteristics Research Report

Target disease: RET fusion‑positive thyroid cancer (molecularly defined subset; most commonly RET fusion‑positive papillary thyroid carcinoma [PTC]) (duke2023fdaapprovalsummary pages 1-3, pekova2023retfusiongenes pages 1-2).
Category: Molecular subtype of differentiated thyroid carcinoma / papillary thyroid carcinoma (duke2023fdaapprovalsummary pages 1-3, pekova2023retfusiongenes pages 1-2).
MONDO ID: A specific MONDO term for “RET fusion‑positive thyroid cancer” was not identified in the retrieved sources; related thyroid cancer MONDO terms exist for other entities (e.g., medullary thyroid gland carcinoma MONDO_0015277, which is typically RET mutation‑driven, not RET fusion‑driven) (parimi2023genomiclandscapeof pages 1-2).

Executive summary

RET fusion‑positive thyroid cancers are thyroid epithelial malignancies driven by oncogenic RET gene rearrangements (RET/PTC). The fusions typically retain the RET kinase domain and use partner‑derived dimerization motifs to enable ligand‑independent RET activation and downstream MAPK/PI3K pathway signaling. RET fusions are enriched in pediatric PTC and in aggressive histologic variants (e.g., diffuse sclerosing PTC), and are associated with high rates of lymph node metastasis and meaningful distant metastasis risk. Clinically, selective RET inhibitors (selpercatinib, pralsetinib) have produced high objective response rates and durable disease control in advanced RET fusion‑positive thyroid cancer, and have become the key real‑world implementation of precision oncology for this subtype (wirth2024durabilityofresponse pages 1-2, clark2023selectiveretinhibitors pages 4-5, pekova2023retfusiongenes pages 1-2).

1. Disease Information

1.1 Definition and overview

RET fusion‑positive thyroid cancer refers to thyroid carcinomas harboring in‑frame chromosomal rearrangements involving RET that generate constitutively active RET fusion oncoproteins (duke2023fdaapprovalsummary pages 3-5). These fusions are most commonly observed in papillary thyroid cancer and are rare across most other solid tumors (duke2023fdaapprovalsummary pages 1-3).

1.2 Key identifiers and ontology mappings

  • Clinical/diagnostic context: RET fusions are molecular alterations in thyroid cancer and are used as predictive biomarkers for RET‑directed therapy selection (carneiro2024predictivebiomarkersin pages 8-9).
  • MeSH/ICD/Orphanet: Specific IDs were not retrieved in the available sources for the molecular subtype.
  • MONDO: No specific MONDO term for the molecular subtype was retrieved (see above).

1.3 Synonyms and alternative names

1.4 Evidence source type

Evidence in this report is derived from aggregated disease‑level resources including multi‑institution cohorts, pan‑tumor NGS datasets, clinical trials (LIBRETTO‑001, ARROW), ClinicalTrials.gov trial records, and FDA regulatory reviews (parimi2023genomiclandscapeof pages 1-2, wirth2024durabilityofresponse pages 1-2, duke2023fdaapprovalsummary pages 1-3, NCT03157128 chunk 1).

2. Etiology

2.1 Disease causal factors

The primary causal factor is an acquired somatic RET gene fusion (RET rearrangement), which creates an oncogenic fusion protein with constitutive kinase activation (desilets2023retalteredcancers—atumoragnostic pages 2-4, pekova2023retfusiongenes pages 11-12).

2.2 Risk factors

Age / pediatric enrichment: In a large cohort (n=993 PTC), RET fusions were detected in 11.4% of PTC overall, and were threefold more frequent in pediatric/adolescent patients (29.8%) than adults (8.7%) (Pekova 2023; published Sep 2023; https://doi.org/10.1530/ERC-23-0117) (pekova2023retfusiongenes pages 1-2).
Radiation exposure: RET/PTC events have been linked to ionizing radiation exposure and radiation‑associated subtypes in thyroid cancer literature (e.g., post‑Chernobyl series and “short radiation latency” associations noted in a 2023 Thai PTC study) (Khonrak 2023; published Apr 2023; https://doi.org/10.3389/pore.2023.1611138) (khonrak2023retrearrangementsare pages 1-2, khonrak2023retrearrangementsare pages 13-13).

2.3 Protective factors

No clear protective genetic or environmental factors specific to acquiring RET fusions were identified in the retrieved sources. One cohort cited an association between coexisting chronic lymphocytic thyroiditis and lower recurrence rates in PTC broadly, but this is not a proven protective factor for RET‑fusion initiation (pekova2023retfusiongenes pages 12-13).

2.4 Gene–environment interactions

The strongest candidate interaction is DNA damage (e.g., radiation) contributing to chromosomal rearrangements that generate RET/PTC fusions, as discussed in the radiation‑associated literature summarized in Thai PTC data and cited post‑Chernobyl series (khonrak2023retrearrangementsare pages 13-13).

3. Phenotypes

3.1 Clinical presentation and phenotype spectrum

RET fusion‑positive thyroid cancer is most often PTC and is frequently associated with aggressive locoregional features.

Aggressive metastatic phenotype (large cohort): In a large Czech cohort of RET fusion‑positive PTC, lymph node metastasis occurred in 75.2% and distant metastasis in 18.6%; metastases were also reported even among microcarcinomas (Pekova 2023; https://doi.org/10.1530/ERC-23-0117) (pekova2023retfusiongenes pages 1-2).

Diffuse sclerosing PTC enrichment and recurrence risk: In diffuse sclerosing PTC (DSPTC), RET fusions were the most common alteration (32% [13/41]), and RET fusion status predicted worse recurrence‑free survival (5‑year RFS 46% vs 84% for other drivers; HR 7.69, p=0.017) (Scholfield 2024; published Jun 2024; https://doi.org/10.1245/s10434-024-15500-9) (scholfield2024definingthegenomic pages 1-3).

Small descriptive cohort: In a retrospective series of operated nodules, RET/PTC fusion‑positive nodules were all malignant (100%) and had a high nodal metastasis rate (80% [4/5]), with 60% diffuse sclerosing variant histology (Tali 2023; published Jun 2023; https://doi.org/10.3390/cancers15133394) (tali2023thedifferencein pages 1-2).

3.2 Suggested HPO terms (examples)

3.3 Quality of life impact

Direct thyroid‑specific QoL metrics for RET fusion‑positive thyroid cancer were not extracted from the retrieved texts. QoL preservation/improvement under selpercatinib was reported across RET‑driven cancers in LIBRETTO‑001, but thyroid‑specific quantitative QoL outcomes were not available in the extracted evidence (wirth2024durabilityofresponse pages 7-7).

4. Genetic / Molecular Information

4.1 Causal genes

  • RET (ret proto‑oncogene), acting as an oncogenic driver via fusion/rearrangement (desilets2023retalteredcancers—atumoragnostic pages 2-4).

4.2 Pathogenic variant class

The defining alteration is a structural rearrangement (gene fusion) producing an in‑frame RET fusion (RET/PTC). Key fusions retain the RET kinase domain (3′ RET) and incorporate a 5′ partner providing dimerization capability (desilets2023retalteredcancers—atumoragnostic pages 2-4, pekova2023retfusiongenes pages 11-12).

4.3 Common fusion partners and frequencies

In a large RET fusion‑positive PTC cohort (n=113 RET+ PTCs):
CCDC6::RET: 59.3% (67/113)
 NCOA4::RET: 22.1% (25/113)
Other partners included FBXO41, SSBP2, ZMYM2 (Pekova 2023; https://doi.org/10.1530/ERC-23-0117) (pekova2023retfusiongenes pages 3-5).

In a pan‑tumor NGS dataset, thyroid papillary carcinoma had RET fusion prevalence 9.09% (109/1199), and across the overall RET fusion cohort common partners included NCOA4 (32.6%) and CCDC6 (29.9%) (Parimi 2023; published Jan 2023; https://doi.org/10.1038/s41698-023-00347-2) (parimi2023genomiclandscapeof pages 1-2).

4.4 Mechanism / functional consequences

RET fusions: 1) retain the RET tyrosine kinase domain in the 3′ fusion portion;
2) are placed under control of a transcriptionally active partner; and
3) often acquire partner‑derived dimerization motifs, enabling ligand‑independent dimerization, phosphorylation, and constitutive signaling (carneiro2024predictivebiomarkersin pages 8-9, desilets2023retalteredcancers—atumoragnostic pages 2-4).

Downstream pathways include MAPK‑ERK, PI3K‑AKT, and JAK‑STAT signaling, supporting proliferative/survival programs (carneiro2024predictivebiomarkersin pages 8-9, chen2024retinhibitorsin pages 1-3).

4.5 Suggested GO biological process terms (examples)

4.6 Suggested Cell Ontology (CL) terms (examples)

  • Thyroid follicular cell — CL:0002262 (suggested; PTC cell of origin)
  • Neoplastic thyroid epithelial cell — not a standard CL term; would be represented as thyroid follicular cell with “neoplastic” context.

5. Environmental Information

5.1 Environmental factors

Ionizing radiation exposure has a longstanding association with RET/PTC rearrangements (notably pediatric and post‑radiation clusters), summarized in contemporary PTC literature and referenced in 2023 Thai PTC analysis (khonrak2023retrearrangementsare pages 1-2, khonrak2023retrearrangementsare pages 13-13).

5.2 Lifestyle factors / infectious agents

No specific lifestyle or infectious etiologies were identified in the retrieved sources.

6. Mechanism / Pathophysiology

6.1 Causal chain (driver → pathway → phenotype)

Trigger/event: Somatic chromosomal rearrangement generating an in‑frame RET fusion (RET/PTC).
Upstream mechanism: Fusion retains the RET kinase domain and partner‑derived interaction motifs → ligand‑independent dimerization and RET autophosphorylation (desilets2023retalteredcancers—atumoragnostic pages 2-4, pekova2023retfusiongenes pages 11-12).
Downstream signaling: Activation of MAPK‑ERK and PI3K‑AKT (and JAK‑STAT) cascades promotes proliferation, survival, migration, and oncogenic transformation (carneiro2024predictivebiomarkersin pages 8-9, chen2024retinhibitorsin pages 1-3).
Clinical phenotype: Higher probability of nodal metastasis and clinically aggressive variants (DSPTC association), with high disease‑specific survival in intensively treated cohorts but higher recurrence risk in certain subtypes (scholfield2024definingthegenomic pages 1-3, pekova2023retfusiongenes pages 1-2).

6.2 Immune system involvement

Evidence linking RET alterations to immune microenvironment changes in PTC exists (RET variation associated with immune infiltration patterns), but this was not specific to RET fusions and is not used here as defining evidence for RET fusion‑positive disease (pekova2023retfusiongenes pages 1-2).

6.3 Molecular profiling

Comprehensive multi‑omics signatures specific to RET fusion‑positive thyroid cancer were not extracted in the available sources.

7. Anatomical Structures Affected

7.1 Organ and tissue level

7.2 Suggested UBERON terms (examples)

8. Temporal Development

8.1 Onset

RET fusion‑positive PTC is enriched in younger patients, including pediatric and adolescent presentations (pekova2023retfusiongenes pages 1-2, khonrak2023retrearrangementsare pages 1-2).

8.2 Progression and course

In a large cohort, metastases (nodal and distant) were frequent, but “true recurrences” were rare (2.4%, adults only) and disease‑specific survival remained high (10‑year 95%) (pekova2023retfusiongenes pages 1-2). In DSPTC, RET fusions identified a higher recurrence‑risk subgroup (5‑year RFS 46%) (scholfield2024definingthegenomic pages 1-3).

9. Inheritance and Population

9.1 Epidemiology

RET fusions are most commonly found in PTC.

Reported prevalence ranges (study‑dependent): * FDA review: RET fusions are observed most commonly in papillary thyroid cancer (5–10%) (Duke 2023; published Sep 15, 2023; https://doi.org/10.1158/1078-0432.CCR-23-0459) (duke2023fdaapprovalsummary pages 1-3).
DNA‑NGS cohort: thyroid papillary carcinoma RET fusion prevalence 9.09% (109/1199) (Parimi 2023; Jan 2023; https://doi.org/10.1038/s41698-023-00347-2) (parimi2023genomiclandscapeof pages 1-2).
 Czech cohort: RET fusions 11.4% (113/993) of PTC; 29.8% pediatric/adolescent vs 8.7% adult (Pekova 2023; Sep 2023; https://doi.org/10.1530/ERC-23-0117) (pekova2023retfusiongenes pages 1-2).

9.2 Inheritance

RET fusions in thyroid cancer are generally somatic driver events rather than inherited. (Germline RET alterations are relevant to MEN2 and medullary thyroid carcinoma, not the RET‑fusion PTC subtype.) (alzumaili2023updateonmolecular pages 5-7).

10. Diagnostics

10.1 Recommended testing approach (current understanding)

Preferred approach: Comprehensive NGS, ideally including DNA and RNA interrogation for fusions, is emphasized as the best method to identify RET fusions and concomitant alterations (desilets2023retalteredcancers—atumoragnostic pages 1-2, desilets2023retalteredcancers—atumoragnostic pages 8-9).

Alternatives/adjuncts: RT‑PCR and FISH may be used when NGS is unavailable, with known limitations (partner dependence, inability to identify partners/breakpoints for FISH) (desilets2023retalteredcancers—atumoragnostic pages 8-9, chen2024retinhibitorsin pages 3-5).

10.2 Test performance and key data

IHC: Sensitivity/specificity for RET IHC reported as 87%/82%, but performance is partner dependent and it is “not recommended as a clinical screening assay for oncogenic RET alterations” (desilets2023retalteredcancers—atumoragnostic pages 8-9).

FISH: Break‑apart FISH sensitivity is fusion‑partner dependent; in one series, thyroid cancer sensitivity was 88%, and partner‑specific sensitivity examples included 100% for KIF5B/CCDC6 but 67% for NCOA4 (desilets2023retalteredcancers—atumoragnostic pages 8-9).

ddPCR (CCDC6::RET): ddPCR improved analytical sensitivity over qRT‑PCR with LoD 128.0 copies/reaction vs 430.7 copies/reaction; in 112 clinical PTC samples ddPCR detected 13.4% (15/112) positives vs 9.8% (11/112) by qRT‑PCR (Chen 2023; Apr 2023; https://doi.org/10.1186/s12885-023-10852-z) (chen2023highlysensitivedroplet pages 1-2, chen2023highlysensitivedroplet pages 2-4).

Commercial thyroid nodule platforms: ThyroSeq v3 (DNA+RNA panel) reports overall performance for nodule classification of 94% sensitivity, 89% specificity, 92% accuracy, and includes RET fusions; Afirma XA uses whole‑transcriptome RNA sequencing and enumerates fusions including CCDC6::RET and NCOA4::RET (Alzumaili 2023; Jun 2023; https://doi.org/10.3390/genes14071314) (alzumaili2023updateonmolecular pages 5-7).

10.3 Differential diagnosis

RET fusions overlap with other fusion‑driven thyroid cancers (e.g., NTRK fusions) and mutation‑driven PTC (BRAF, RAS). Molecular testing distinguishes these entities for targeted therapy selection (alzumaili2023updateonmolecular pages 5-7, pekova2023retfusiongenes pages 1-2).

11. Outcome / Prognosis

Disease‑specific survival (large cohort): In RET fusion‑positive PTC, 2‑, 5‑, 10‑year disease‑specific survival were 99%, 96%, 95%, despite high metastatic burden, suggesting aggressive biology but potentially favorable survival with intensive multimodal management (pekova2023retfusiongenes pages 1-2).

Subtype‑specific recurrence risk: In DSPTC, RET fusions predicted worse recurrence‑free survival (5‑year RFS 46%) and were the only independent recurrence predictor (HR 7.69) (scholfield2024definingthegenomic pages 1-3).

12. Treatment

12.1 Targeted therapy (current standard for advanced RET fusion‑positive disease)

Selpercatinib (RET inhibitor)

Regulatory indication (FDA): FDA accelerated approval (May 8, 2020) includes adult and pediatric (≥12 years) patients with advanced/metastatic RET fusion‑positive thyroid cancer requiring systemic therapy and RAI‑refractory (if RAI appropriate) (Duke 2023; https://doi.org/10.1158/1078-0432.CCR-23-0459) (duke2023fdaapprovalsummary pages 1-3).

Dose concept (FDA review): 120 mg orally BID if <50 kg; 160 mg orally BID if ≥50 kg (duke2023fdaapprovalsummary pages 3-5).

Efficacy (LIBRETTO‑001 long‑term update): At January 2023 cutoff, RET fusion‑positive thyroid cancer cohort (n=66) demonstrated:
ORR 95.8% in treatment‑naïve patients (n=24) and 85.4% in previously treated patients (n=41) (Wirth 2024; published Sep 2024; https://doi.org/10.1200/JCO.23.02503) (wirth2024durabilityofresponse pages 7-7).
 Median PFS: not reached (treatment‑naïve) and 27.4 months (pretreated) (wirth2024durabilityofresponse pages 1-2, wirth2024durabilityofresponse pages 7-7).

Pralsetinib (RET inhibitor)

ARROW trial efficacy (previously treated RET fusion+ thyroid cancer): ORR 90.9% (95% CI 70.8–98.9) in 22 previously treated patients (review summary; Chen 2024; published Oct 2024; https://doi.org/10.3389/fendo.2024.1346476) (chen2024systemictreatmentsfor pages 7-8).
Another synthesis reports ORR 89% (95% CI 52–100) in RET fusion‑positive thyroid cancer cohorts (Clark 2023; published Dec 2023; https://doi.org/10.3390/cancers16010031) (clark2023selectiveretinhibitors pages 4-5).

Key toxicities (grade ≥3 TRAEs, thyroid cancer population in summary): hypertension 17%, neutropenia 13%, lymphopenia 12%, anemia 10%; pneumonitis 4%; discontinuation 4%; treatment‑related death 1% (clark2023selectiveretinhibitors pages 4-5).

12.2 Treatment resistance (mechanisms and emerging strategies)

Acquired resistance to selective RET inhibitors may involve: * On‑target RET mutations, especially solvent‑front RET G810 substitutions (G810X); also RET L730V/I, Y806, V738 alterations (desilets2023retalteredcancers—atumoragnostic pages 15-16).
Bypass mechanisms, including MET amplification and MAPK reactivation via emergent KRAS/NRAS/BRAF* alterations (desilets2023retalteredcancers—atumoragnostic pages 15-16).
Next‑generation RET inhibitors are being developed with activity against solvent‑front and gatekeeper mutants (e.g., preclinical development described in 2023 review; APS03118 potency against G810 and V804 mutants, with PDX/intracranial models) (clark2023selectiveretinhibitors pages 9-11).

12.3 Suggested MAXO terms (examples)

  • Targeted therapy — MAXO:0000058 (suggested)
  • Tyrosine kinase inhibitor therapy — MAXO:0000647 (suggested)
  • Molecularly targeted therapy based on gene fusion — (suggested; if available in MAXO)

12.4 Suggested CHEBI entities

The CHEBI IDs for selpercatinib and pralsetinib were not retrieved in the available sources.

13. Prevention

Primary prevention for RET fusion acquisition is not established. Secondary prevention consists of early detection and appropriate molecular testing to enable precision therapy. Specific screening strategies for RET fusions in the general population are not described in the retrieved sources.

14. Other species / natural disease

Not identified in retrieved sources.

15. Model organisms / experimental models

Selpercatinib preclinical models: FDA review notes selpercatinib activity in in vitro/in vivo models with CCDC6‑RET, KIF5B‑RET, and RET resistance/driver mutations (RET V804M, M918T), and in a mouse intracranial model with a patient‑derived RET fusion‑positive tumor (Duke 2023; https://doi.org/10.1158/1078-0432.CCR-23-0459) (duke2023fdaapprovalsummary pages 3-5).

Engineered resistance models: Engineered Ba/F3 fusion models (e.g., Ba/F3 KIF5B‑RET) and derived resistant lines have been used to characterize on‑target resistance mutations under RET inhibitor pressure (Spitaleri 2024; published Aug 2024; https://doi.org/10.3390/cancers16162877) (spitaleri2024nonsmallcelllungcancers pages 11-12).

PDX and intracranial orthotopic models for next‑gen inhibitors: A 2023 review describes PDX and intracranial orthotopic models including CCDC6‑RET and CCDC6‑RET V804M, demonstrating feasibility of brain‑penetrant next‑generation RET inhibition strategies aimed at resistance (clark2023selectiveretinhibitors pages 9-11).

Evidence table (structured summary)

Table (click to expand)
Study (first author, year) Population/cohort Method Key findings (with exact numbers) URL/DOI
Parimi, 2023 Pan-tumor cohort of 891 RET fusion-positive advanced solid tumors; thyroid papillary carcinoma subset Tissue-based DNA hybrid-capture NGS; subset with liquid biopsy hybrid-capture NGS RET fusions were most frequent in lung adenocarcinoma and thyroid papillary carcinoma; thyroid papillary carcinoma prevalence was 9.09% (109/1199). In the pan-tumor RET+ cohort, common partners included NCOA4 32.6% and CCDC6 29.9%. Tissue-liquid concordance for RET fusion detection was 100% (8/8) when composite tumor fraction was >1% (parimi2023genomiclandscapeof pages 1-2) https://doi.org/10.1038/s41698-023-00347-2
Pekova, 2023 1,564 thyroid tissue samples including 1,164 carcinomas and 993 PTCs; pediatric and adult patients Driver testing followed by extensive RET fusion analysis using NGS and real-time PCR RET fusions were detected exclusively in PTC, in 113/993 (11.4%) patients; prevalence was 29.8% in pediatric/adolescent patients vs 8.7% in adults. 20 RET fusion types were identified. Aggressiveness: lymph node metastasis 75.2%, distant metastasis 18.6%, true recurrences 2.4%. Disease-specific survival: 2-year 99%, 5-year 96%, 10-year 95% (pekova2023retfusiongenes pages 1-2) https://doi.org/10.1530/ERC-23-0117
Pekova, 2023 RET fusion-positive PTC subset from the above cohort (n=113) Targeted RNA sequencing panels with real-time PCR confirmation Fusion partners: CCDC6 67/113 (59.3%), NCOA4 25/113 (22.1%); additional recurrent/novel partners included FBXO41, SSBP2, ZMYM2. Cohort characteristics: 75.2% female, mean age 32.6 ± 17.4 years, mean tumor size 21.8 ± 12.6 mm (pekova2023retfusiongenes pages 3-5) https://doi.org/10.1530/ERC-23-0117
Chen, 2023 TCGA PTC cohort (402) and clinical PTC samples (112) ddPCR assay for CCDC6::RET vs qRT-PCR; Sanger confirmation In TCGA, RET fusions were present in 25/402 (6.2%) PTCs; CCDC6::RET accounted for 15/25 (60%) of RET-positive cases. In clinical samples, qRT-PCR detected 11/112 (9.8%) CCDC6::RET-positive cases, while ddPCR detected 15/112 (13.4%), adding 4 extra positives. Limit of detection: 128.0 copies/reaction for ddPCR vs 430.7 copies/reaction for qRT-PCR (chen2023highlysensitivedroplet pages 1-2, chen2023highlysensitivedroplet pages 2-4) https://doi.org/10.1186/s12885-023-10852-z
Khonrak, 2023 Thai PTC cohort (n=83) qRT-PCR on FFPE samples for CCDC6::RET and NCOA4::RET Background prevalence noted as ~10–40% of adult PTC and 45–60% of pediatric/adolescent sporadic PTC; CCDC6 and NCOA4 together account for ~90% of RET::PTC fusions. Phenotype: CCDC6::RET associated with classic subtype and absence of angio/lymphatic invasion; NCOA4::RET associated with tall-cell subtype, angio/lymphatic invasion, and lymph node metastasis (khonrak2023retrearrangementsare pages 1-2) https://doi.org/10.3389/pore.2023.1611138
Tali, 2023 Molecularly tested operated thyroid nodules; RET/PTC-positive nodules (n=5) Retrospective single-center study using preoperative molecular testing and final pathology All 5/5 (100%) RET/PTC nodules were malignant and Bethesda V/VI. Histology: 60% (3/5) diffuse sclerosing variant, 40% (2/5) classical PTC. Aggressiveness: 80% (4/5) lymph node metastasis, 20% (1/5) extrathyroidal extension; one nodal metastasis case had extranodal spread (tali2023thedifferencein pages 4-6, tali2023thedifferencein pages 1-2) https://doi.org/10.3390/cancers15133394
Scholfield, 2024 Diffuse sclerosing papillary thyroid carcinoma (DSPTC) tumors (n=41) MSK-IMPACT 505-gene panel sequencing RET fusions were the most common alteration: 32% (13/41). RET fusion-positive tumors occurred at younger age and had more aggressive features and higher T-stage. Outcome: 5-year recurrence-free survival 46% vs 84% for other drivers; multivariable analysis: RET fusion status independent predictor of recurrence (HR 7.69, p=0.017) (scholfield2024definingthegenomic pages 1-3) https://doi.org/10.1245/s10434-024-15500-9
Selpercatinib (LIBRETTO-001), Wirth, 2024 RET fusion-positive thyroid cancer in LIBRETTO-001; treatment-naïve (n=24) and pretreated (n=41) Phase I/II clinical trial long-term update At January 2023 cutoff, ORR was 95.8% (95% CI 78.9–99.9) in treatment-naïve patients and 85.4% (95% CI 70.8–94.4) in pretreated patients; complete responses 20.8% and 12.2%, respectively. Median follow-up: 24.9 months (naïve) and 30.4 months (pretreated). Median PFS: not reached (naïve) and 27.4 months (pretreated). 3-year PFS 87.3% in treatment-naïve TC; 3-year overall survival 94.4% (naïve) and 65.5% (pretreated) (wirth2024durabilityofresponse pages 1-2, wirth2024durabilityofresponse pages 7-7, wirth2024durabilityofresponse media 08850bf1) https://doi.org/10.1200/JCO.23.02503
Selpercatinib (regulatory summary), Duke, 2023 FDA summary referencing prior thyroid approval and broader RET fusion-positive solid tumor activity FDA review of LIBRETTO-001 FDA notes RET fusions are seen most commonly in papillary thyroid cancer at 5–10%. For thyroid cancer, prior approval covered adult and pediatric patients ≥12 years with advanced/metastatic RET fusion-positive thyroid cancer requiring systemic therapy and RAI-refractory if RAI appropriate. Selpercatinib activity supported by preclinical models including CCDC6-RET (duke2023fdaapprovalsummary pages 3-5, duke2023fdaapprovalsummary pages 1-3) https://doi.org/10.1158/1078-0432.CCR-23-0459
Pralsetinib (ARROW), Clark, 2023 RET fusion-positive thyroid cancer cohort in ARROW (n=20 enrolled; efficacy summarized across thyroid cohorts) Phase I/II multicohort trial summary Reported ORR in RET fusion-positive thyroid cancer was 89% (95% CI 52–100). Safety in RET-altered thyroid cancer: grade ≥3 TRAEs included hypertension 17%, neutropenia 13%, lymphopenia 12%, anemia 10%; serious TRAEs in 15%; pneumonitis in 4%; discontinuation due to TRAEs 4%; treatment-related death 1% (clark2023selectiveretinhibitors pages 4-5) https://doi.org/10.3390/cancers16010031
Pralsetinib (ARROW), Chen, 2024 Previously treated RET fusion-positive thyroid cancer patients (n=22) Review summarizing ARROW (NCT03037385) ORR was 90.9% (95% CI 70.8–98.9) in 22 previously treated RET fusion-positive thyroid cancer patients; review notes FDA approval for RET fusion-positive thyroid cancer in December 2020 (chen2024systemictreatmentsfor pages 7-8) https://doi.org/10.3389/fendo.2024.1346476
Pralsetinib (ARROW), Desilets, 2023 Previously treated RET fusion-positive thyroid cancer cohort Tumor-agnostic review summarizing ARROW Reported ORR for previously treated RET fusion-positive thyroid cancer was 89%. Common grade 3–4 adverse events across studies included neutropenia 13–31%, hypertension 7–17%, anemia 10–14%, lymphopenia 9–12%, increased creatine phosphokinase 6%, and treatment-emergent pneumonitis 4% (desilets2023retalteredcancers—atumoragnostic pages 13-15) https://doi.org/10.3390/cancers15164146

Table: This table compiles key cohort-level evidence on RET fusion prevalence, dominant fusion partners, clinicopathologic aggressiveness, and selective RET inhibitor outcomes in RET fusion-positive thyroid cancer. It is useful as a compact evidence map for diagnosis, prognosis, and treatment selection.

Key “expert opinion” synthesis (from authoritative sources)

  • Testing: Comprehensive NGS (preferably DNA+RNA) is emphasized as the best way to identify RET fusions and concurrent alterations; IHC is not recommended as a screening assay due to variable performance (desilets2023retalteredcancers—atumoragnostic pages 8-9, chen2024retinhibitorsin pages 3-5).
  • Clinical importance: RET fusions are common enough in PTC to justify systematic testing strategies, especially in advanced disease where selective RET inhibitors provide high response rates (duke2023fdaapprovalsummary pages 1-3, wirth2024durabilityofresponse pages 1-2).
  • Therapeutic landscape: Selective RET inhibitors are now standard precision options, but resistance via RET solvent‑front mutations and bypass pathways motivates development of next‑generation inhibitors and combination approaches (desilets2023retalteredcancers—atumoragnostic pages 15-16, clark2023selectiveretinhibitors pages 9-11).

Notable gaps / limitations of retrieved evidence

  • A specific MONDO/MeSH/ICD identifier for the fusion‑positive molecular subtype was not retrieved.
  • Some requested items (thyroid‑specific QoL outcomes; pralsetinib DoR/PFS; detailed treatment algorithms from society guidelines) were not present in the accessible text segments and would require targeted retrieval of the primary ARROW thyroid manuscript and thyroid cancer clinical guidelines.

References

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