碘-131治疗（¹³¹I therapy，RAI）作为分化型甲状腺癌（differentiated thyroid cancer，DTC）全切术后的重要治疗手段，目前仍存诸多争议：如辅助治疗（¹³¹I adjuvant therapy，RAT）因其目标病灶无法可视化致适应证欠清、获益未明；晚期DTC的分子驱动机制及其临床意义特别是与放射性碘难治性（radioactive iodine-refractory, RAIR）的联系未明、不同基因分子亚组对碘-131清灶治疗的治疗响应模式各异，特异性分子靶点抑制剂对晚期DTC疗效和安全性仍有待进一步探索等。因此，本系列研究拟围绕分子特征在DTC精细化诊疗中的应用，旨在达成以下目标：

1. 通过临床病理、血清学、核医学分子影像学等特征评价RAT疗效，进一步明确其适应证人群；

2. 探索在局晚/远处转移性DTC（distant metastasis-DTC，DM-DTC）患者中融合基因分子特征的临床意义及其与RAIR的联系；

3. 探索不同基因亚组在晚期摄碘性DM-DTC的¹³¹I清灶治疗中的疗效差异；

4. 探索RET融合阳性亚组在晚期摄碘性DM-DTC中经单次和多次¹³¹I清灶治疗的疗效差异；

5. 评估RET抑制剂（普拉替尼和塞普替尼）在RET融合变异型进展性RAIR-DTC的疗效（影像学/生化）、安全性及诱导分化潜能。

方法：

1. 多中心回顾性队列现行指南推荐的中高危RAT适应证人群（n=599），通过随访期间的甲状腺球蛋白（thyroglobulin，Tg）水平、影像学和¹³¹I治疗后全身扫描（post-therapy whole-body scan，Rx-WBS）等结果，评价患者的术后疾病状态、即时治疗目标以及在RAT后12个月的治疗反应；

2. 对全年龄段局晚/DM-DTC患者（n=278）进行二代测序（ThyroLead panel），分析其中融合基因与临床特征及RAIR的相关性；

3. 回顾性纳入158例摄碘性DM-DTC患者，比较RET融合基因与其他不同基因亚型的¹³¹I治疗后的无进展生存（progression-free survival，PFS）；

4. 探索RET融合型DM-DTC患者RAI治疗频次与治疗后PFS的关系，及影响预后的相关因素；

5. 进行真实世界研究评估6例进展性RET融合型RAIR-DTC患者接受普拉替尼/塞普替尼治疗的影像学、血清学生化疗效与安全性，并探索其诱导分化作用。

结果：

1. 49.75%的中高危患者术后疾病状态为疗效满意(excellent response，ER）和疗效不确切(indeterminate response，IDR)，此类患者经即时治疗目标验证后证实RAT治疗仅靶向残甲组织、而非亚临床病灶，治疗12个月后仍有95.64%患者维持ER/IDR；45.78%术后疾病状态BIR的患者RAT12月后转变为ER/IDR。其中T1/T2分期、甲状腺包膜侵犯、非多发病灶、手术次数、Rx-WBS上未见远处转移是术后BIR转变为12个月ER/IDR的独立影响因素（所有P<0.05）。此外，相比3.7 GBq剂量组的患者，接受>3.7 GBq剂量的患者从术后疾病状态BIR转化为12个月ER/IDR的概率更大（P<0.001）。

2. 在局晚/DM-DTC队列中，融合基因占29.86%（86.75%为RET融合），与更晚期的N（P=0.017）、M分期相关（P=0.016）。儿童青少年（pediatric DTC，pDTC）中融合基因发生率更高（P=0.003），且与RAIR（P=0.017）相关；而成人（adult DTC，aDTC）中RAIR主要与TERT突变相关（P<0.001）。

3. 在摄碘性DM-DTC队列中，RET融合组相比点突变组的确诊年龄更小（中位25.84岁 vs. 44.70岁，P<0.001），相比RET融合阴性组的男性占比更高（49.12% vs 33.66%，P=0.042）。和点突变/未突变组相比，RET融合阳性组接受RAI后的PFS并未见到显著差异（P均>0.5）。相比未突变组，点突变组接受RAI后的PFS显著降低（P=0.007），其中RAS（n=9）和TERT突变组(n=8)相比未突变组PFS显著降低（P=0.031，0.006）。

4. 在57例RET融合组患者中，经单次RAI后的PFS已不劣于多次RAI（P=0.617）。

5. 普拉替尼/塞普替尼治疗进展性RET融合型RAIR-DTC的影像学客观缓解率达83.33%，中位PFS为8个月，66.67%患者血清学出现Tg和/或TgAb水平下降。1例患者经RAT治疗后出现诱导再分化、逆转摄碘的现象。普拉替尼更易出现血液系统毒性，塞普替尼以代谢异常为主。

结论：

本系列研究探索了分子特征在DTC患者碘治疗中的应用价值，主要有以下发现：

1. 术后综合评价（尤其是血清学和核医学分子影像学等特征）可精细化识别患者术后疾病状态，为RAT的精细化决策提供依据。术后ER/IDR的中危患者或可免于激进的RAT，而术后BIR者是RAT的适应证人群，可从RAT（>3.7 GBq）治疗中获益。

2. 不同于成人RAIR的分子机制，pDTC中RET融合基因分子特征可能在RAIR的发生中起主导作用。

3. RET融合性DM-DTC患者，即使病灶摄碘，但相较于其他BRAF等点突变亚组，其经RAI治疗后的预后并未显著改善，并常呈现摄碘但进展的RAIR特征。提示RAI治疗决策中整合基因分子特征及摄碘性分子影像学特征的重要性。

4. RET融合型摄碘性DM-DTC人群经单次RAI的PFS已不劣于多次RAI。因此，我们需要重视这类患者碘治疗前后的评估和随访管理，审慎平衡每次RAI的治疗获益和风险。

5. 特异性RET抑制剂治疗在RET融合型RAIR-DTC患者展现了鲜明的疗效，耐受性好，其诱导RAIR病灶再分化、恢复摄碘的潜力可能为此类患者尤其是前线耐药者提供新的治疗选择。

Background and Purpose:

As a critical postoperative treatment for differentiated thyroid cancer (DTC), iodine-131 therapy (RAI) remains controversial in several areas: (1) The unclear indications and uncertain benefits of adjuvant RAI (RAT) due to the inability to visualize target lesions; (2) The molecular drivers of advanced DTC, particularly their clinical significance and relationship with radioactive iodine-refractory (RAIR) status, remain poorly understood; (3) Heterogeneous treatment responses to RAI across molecular subgroups; and (4) The efficacy and safety of molecular-targeted inhibitors in advanced DTC require further exploration.
This study series aimed to investigate the role of molecular profiling in precision management of DTC, with the following objectives:

1. Evaluate RAT efficacy using clinicopathological, serological, and molecular imaging features to refine indications.

2. Explore the clinical significance of fusion gene profiles in locally advanced/metastatic DTC (DM-DTC) and their association with RAIR.

3. Compare therapeutic outcomes of RAI across genetic subgroups (e.g., RET fusion vs. others) in iodine-avid DM-DTC.

4. This study explores the relationship between RAI treatment frequency and progression-free survival (PFS) in RET fusion-positive DM-DTC patients, along with relevant prognostic factors.

5. Assess the efficacy, safety, and redifferentiation potential of RET inhibitors (pralsetinib/selpercatinib) in progressive RET fusion-positive RAIR-DTC.

Methods:

1. A multicenter retrospective cohort (n=599) of intermediate-to-high-risk RAT candidates was analyzed using thyroglobulin (Tg) levels, imaging, and post-therapy whole-body scans (Rx-WBS) to assess postoperative disease status, treatment goals, and 12-month responses.

2. Next-generation sequencing (ThyroLead panel) was performed in 278 locally advanced/DM-DTC patients to correlate fusion genes with clinical features and RAIR.

3. Retrospective analysis of PFS after RAI in 158 iodine-avid DM-DTC patients, stratified by genetic subgroups.

4. Investigating the relationship between RAI therapy frequency and post-treatment PFS in 57 RET fusion-positive DM-DTC patients, and exploring relevant prognostic factors.

5. Real-world evaluation of 6 progressive RET fusion RAIR-DTC patients treated with pralsetinib/selpercatinib for radiological/biochemical responses, safety, and redifferentiation potential.

Results:

1. Among intermediate-to-high-risk patients, 49.75% achieved excellent/indeterminate response (ER/IDR) postoperatively. RAT targeted residual thyroid tissue rather than subclinical disease in these patients, with 95.64% maintaining ER/IDR at 12 months. 45.78% of patients with biochemical incomplete response (BIR) converted to ER/IDR after RAT. T1/T2 staging, capsular invasion, unifocal disease, surgeries, absence of distant metastases on Rx-WBS, and RAI doses >3.7 GBq independently predicted BIR-to-ER/IDR conversion (all P<0.05).

2. Fusion genes (86.75% RET fusions) occurred in 29.86% of locally advanced/DM-DTC cases, correlating with advanced N (P=0.017) and M stages (P=0.016). Pediatric DTC (pDTC) showed higher fusion rates (P=0.003) linked to RAIR (P=0.017), while adult DTC (aDTC) RAIR associated with TERT mutations (P<0.001).

3. RET fusion DM-DTC patients were younger (median 25.84 vs. 44.70 years, P<0.001) and more frequently male (49.12% vs. 33.66%, P=0.042) than other subgroups. Compared to the point-mutation and unmutated groups, the RET fusion-positive cohort showed no significant difference in PFS (all P>0.5). However, the point-mutation group exhibited significantly reduced PFS after RAI versus the unmutated group (P=0.007), with RAS-mutated (n=9) and TERT-mutated subgroups (n=8) demonstrating particularly significant PFS reduction compared to unmutated controls (P=0.031 and P=0.006, respectively).

4. Single-dose RAI achieved comparable PFS to multiple doses in RET fusion cases (P=0.617).

5. RET inhibitors demonstrated an 83.33% objective response rate, median PFS of 8 months, and Tg/TgAb reduction in 66.67% of RAIR-DTC patients. One case showed RAI-redifferentiation post-treatment. Pralsetinib predominantly caused hematologic toxicity, while selpercatinib induced metabolic abnormalities.

Conclusions:

1. Postoperative multimodal assessment (serological/molecular imaging) optimizes RAT decision-making: Intermediate-risk ER/IDR patients may avoid aggressive RAT, while BIR patients benefit from higher-dose RAI (>3.7 GBq).

2. RET fusion drives RAIR in pDTC, contrasting with TERT-driven RAIR in aDTC.

3. Despite iodine avidity, RET fusion DM-DTC shows RAIR-like progression post-RAI, emphasizing the need for molecular-integrated treatment strategies.

4. In RET fusion-positive RAI-avid DM-DTC patients, PFS following a single RAI therapy has proven non-inferior to that after multiple RAI treatments. Hence, this population requires careful assessment and follow-up management before and after radioiodine therapy, with each subsequent RAI administration necessitating judicious weighing of therapeutic benefits against potential risks.

5. RET inhibitors demonstrate the significant efficacy and redifferentiation potential in RET fusion RAIR-DTC, offering new therapeutic options for refractory cases.