genotype-driven neoadjuvant therapy for locally advanced thyroid cancer: a real-world cohort study

Conditions: Thyroid Neoplasms

Summary: 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.

Eligibility criteria:
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).

Keywords: locally advanced neoadjuvant therapy real-world study braf v600e ret fusion vegf-tki immunotherapy conversion surgery r0 resection precision oncology real-world evidence conversion therapy