Interpretation of the 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer: precision treatment guided by genotyping

doi:10.19401/j.cnki.1007-3639.2025.09.003

Abstract

Abstract:

The “2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer” introduce significant updates in genotyping. This article systematically interpreted the role and clinical applications of genotyping in pre-diagnostic differentiation, post-diagnostic familial analysis, surgical approach guidance, postoperative recurrence risk stratification, as well as targeted therapy and immunotherapy with a focus on mutation-based medical decision-making. Key updates on standardized genotyping applications include: ① In pathological diagnosis, genotyping was first applied in pathological differentiation. The 2025 ATA guidelines further clarify the distribution patterns of different genetic mutations across pathological subtypes, enabling more precise classification, particularly for tumors of very low malignant potential, to avoid overtreatment.② In familial analysis and genetic counseling, systematic familial evaluation is recommended post-diagnosis. The 2025 ATA guidelines propose strict clinical evidence-based categorization and selective germline genetic testing, with tailored genetic counseling strategies based on genotype. ③ In surgical approach and recurrence risk stratification, the 2025 ATA guidelines refine the auxiliary role of genotyping in surgical decision-making and recurrence risk stratification, reiterating that genotyping complements traditional risk stratification systems. ④ In targeted therapy, the 2025 ATA guidelines establish genotyping-guided precision therapy, mandating genetic testing for all radioiodine-refractory differentiated thyroid cancer (DTC) patients before targeted therapy to select mutation-specific agents. For patients progressing on target-specific drugs, re-biopsy is recommended to identify actionable targets. If no treatable target exists, multi-kinase inhibitors are advised. ⑤ In immunotherapy, pre-treatment genetic testing is recommended, with immunotherapy indicated for radioiodine-refractory DTC patients exhibiting high tumor mutational burden (TMB-H). This article provided a comprehensive review and in-depth analysis of the clinical applications of genotyping in DTC management as outlined in the 2025 ATA guidelines.

Key words: Differentiated thyroid cancer, Guideline, Genotyping, Clinical Management, Precision diagnosis and treatment

CLC Number:

R736.1

WANG Hao, LIANG Jun. Interpretation of the 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer: precision treatment guided by genotyping[J]. China Oncology, 2025, 35(9): 833-840.

Figures/Tables 4

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Pathological type	BRAF^V600E	NRAS\HRAS\KRAS	TERT	TP53	RET	PAX8/PPARγ	Note
NIFTP	None (BRAF^K601E seen)	60%	Rare	Rare	Rare	30%	THADA fusion (30%)
PTC	46%~90%	10%-20%	10%-15%	Rare	10%-15%	Rare	NTRK fusion (7%)
IEFVPTC	Common	70%	10%-15%	Rare	Uncommon	40%	Molecular profile similar to FTC
FTC	Rare	30%-45%	10%-15%	Rare	Rare	25%	PIK3CA, PTEN mutations also occur
OTC	Rare	Visible	10%-15%	Rare	Rare	Rare	Characterized by mitochondrial DNA mutations, near-haploid genome
PDTC/DHTC	Common	Common	Common	Common	Uncommon	Uncommon	Often arise from PTC/FTC progression, harbor additional high-risk mutations
ATC	25%-70%	15%-40%	65%-75%	50%-70%	Rare	Rare	Higher tumor mutation burden, harbors multiple high-risk mutations

Syndrome (gene)	Histology	Other features	Lifetime risk	Germline genetic testing
Cowden syndrome/PHTS (PTEN)	FTC^*, PTC	Breast cancer, endometrial cancer, goiter, macrocephaly	3%-10%	Recommended
DICER1 tumor predisposition (DICER1)	PTC, FTC^*, PDTC	Pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal tumors	Up to 12%	Recommended
FAP (APC)	CMTC, PTC	Colon polyposis, CHRPE, desmoids	OR=9.2 (CI: 2.1-34.7)	Recommended
Carney complex (PRKAR1A)	FTC^*, PTC	Pigmented abnormalities of the skin, myxomas, schwannomas, and endocrine tumors	Unknown	Recommended
Werner syndrome (WRN)	FTC^*, PTC	Premature aging, cataracts, DM, other cancers	Unknown	Recommended
Unexpected findings in tumor gene testing	DTC	Suspected hereditary pathogenic gene mutations (e.g., PTEN, RET, APC, etc.)	Unknown	Recommended
non-syndromic FNMTC	DTC	If ≥3 family members have thyroid cancer without the aforementioned high-risk factors.	Unknown	If with history of other malignant tumors, recommended.
Non-FNMTC	DTC	If≤2 family members have thyroid cancer without the aforementioned high-risk factors.	Unknown	Not recommended

Type	Early Genomic changes	Events in combination with early changes associated with progression
PTC	Mutation: BRAF^V600E, RAS, BRAF non-V600E; Fusion: BRAF, RET, ALK, NTRK1/3; Other: 1q gain, 22q loss	Mutation: TERT promoter (C228T/C250T), TP53, RBMI0, CDKN2B, PIK3CA, PLEKSH1p, AKT1; Other: CDKN2A and CDKN2B loss, increased APOBEC3B activity, global DNA hypomethylation
FTC	Mutation: RAS, DICER1, EIF1AX, PTEN, GNAS, BRAF non-V600E; Fusion: PPARγ, THADA; Other: amplification of the long arm of chromosome 7, and deletion of the long arm of chromosome 22	Mutation: TERT promoter (C228T/C250T), TP53, RB1, RBMIO, CCNE1; Other: CDKN2A and CDKN2B loss, global DNA hypomethylation
OTC	Mutation: Mitochondrial DNA, RAS, DAXX, ARHGGAP35, APC, FAT11, CDKN1A, PTEN, GNAS; Fusion: PRKAB1, VPRREB3, PANX1; Other: Chromosomal loss, near haploid with or without genome wide duplication	Mutation: TERT promoter (C228T/C250T); TP53, FAT1, AGAp2, MTOR, AKT2, MT2C, KEAP1, TBX3, CDKNIB, NFL, PDGFRA, CD274, JAK2; Other: CDKN2A and CDKN2B loss

Driver gene mutation	First-line treatment	Second-line treatment
Non-NTRK/RET/ALK/BRAF^V600E	Lenvatinib sorafenib	Cabozantinib
NTRK Fusion	Larotrectinib, entrectinib	Lenvatinib
RET Fusion	Selpercatinib, pralsetinib	Lenvatinib
ALK Fusion	Crizotinib, alectinib, lorlatinib	Lenvatinib
BRAF^V600E mutation	If tolerating MKI: MKI	Vemurafenib, dabrafenib+trametinib, encorafenib+binimetinib
	If not tolerating MKI: vemurafenib, dabrafenib+ trametinib, encorafenib+binimetinib	None