Genotype-Driven Neoadjuvant Therapy for Locally Advanced Thyroid Cancer: A Real-World Cohort Study

A Multicenter Prospective-Retrospective Real-World Study Evaluating Conversion-to-Surgery and Survival After Genotype-Matched Neoadjuvant Systemic Therapy in Locally Advanced Thyroid Carcinoma

This multicenter registry tests whether genomically matched neoadjuvant therapy (1-4 cycles tailored to BRAF V600E, RET fusion/mutation, isolated TERT mutation, triple-negative BRAF/RET/TERT, or ICI ± TKI) can render locally advanced, initially unresectable-or high-morbidity-thyroid cancers operable. The primary endpoint is conversion-to-surgery; key secondaries are R0/1 margin rate and 12-month event-free survival, with propensity-score weighting correcting cohort imbalances. Findings aim to define a precision-guided neoadjuvant standard for down-staging advanced thyroid tumors.

This multicenter, prospective-retrospective registry will determine whether genotype-matched neoadjuvant systemic therapy can convert locally advanced, initially unresectable or high-morbidity thyroid cancers to successful surgery. Patients receive one to four 28-day cycles of treatment chosen according to actionable genomic alterations-BRAF V600E, RET fusion, RET point mutation, isolated TERT promoter mutation, "BRT triple-negative" (wild-type for BRAF/RET/TERT), or immune-checkpoint blockade ± TKI-before reassessment by a multidisciplinary team.

Primary outcome is the conversion-to-surgery rate. Key secondary outcomes include R0/1 (margin-negative) resection rate and 12-month event-free survival, defined as absence of progression, unresectability at planned surgery, recurrence, or death. Propensity-score weighting will balance baseline differences among cohorts and permit adjusted comparisons. Results will clarify the role of targeted and immunologic agents in down-staging advanced thyroid tumors and may establish a precision-guided neoadjuvant standard of care.

Inclusion Criteria:

1. Age ≥ 18 years at enrollment.

2. Histologically or cytologically confirmed thyroid carcinoma that meets ≥ 1 of the following:

   • Radioactive-iodine-refractory differentiated thyroid carcinoma (DTC)
   • Medullary thyroid carcinoma (MTC)
   • Anaplastic or poorly differentiated thyroid carcinoma (ATC/PDTC)
   • Other locally advanced / metastatic thyroid malignancy deemed incurable by surgery alone.

3. Disease judged unresectable or entailing prohibitively high-morbidity surgery at baseline by a multidisciplinary thyroid-oncology board.

4. Documented molecular or immunophenotype qualifying for ≥ 1 study arm:

   • BRAF V600E mutation
   • RET gene fusion
   • RET activating point mutation (e.g., M918T)
   • NTRK1/2/3 fusion
   • Isolated TERT-promoter mutation with no BRAF/RET/NTRK alterations
   • Driver-negative / VEGFR-wild type ("triple-negative")
   • PD-L1 expression ≥ 1 % OR progression after prior multi-kinase inhibitor (MKI).

5. ECOG Performance Status 0-2.

6. At least one measurable lesion per RECIST v1.1 / iRECIST (MTC with calcitonin/CEA evaluable disease accepted).

7. Written informed consent obtained.

Exclusion Criteria:

1. Untreated or symptomatic CNS metastases; patients with treated, stable lesions ≥ 4 weeks and off corticosteroids are eligible.
2. Pregnant or breastfeeding. Women and men of child-bearing potential must agree to effective contraception during study and for ≥ 120 days after last dose (≥ 180 days for men after dabrafenib/trametinib).