Differentiated thyroid cancer (DTC) is the most common cancer of the thyroid. DTC includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and oncocytic thyroid carcinoma (OTC). DTC generally has a good prognosis. For more difficult to treat thyroid cancers newer targeted therapies may be an option.

The American Thyroid Association (ATA) recently updated their clinical practice guidelines on differentiated thyroid cancer. Included in this update are new sections on genetic and molecular testing and thyroid cancer survivorship. While this guideline is quite comprehensive this article will only review a small portion of the available information, focusing on genetic testing and targeted therapies.

Guidelines Referenced:
Major Changes and Key Takeaways (2015-2025)
  • Genetic and Molecular Testing
    • The new 2025 ATA guideline expanded on previous recommendations for genetic and molecular testing as follows:
      • Germline testing may be offered to certain patients.
      • Patients with Familial Non-Medullary Thyroid Cancer (FNMTC) should have regular neck examinations and may undergo screening ultrasounds (US).
      • Biomarker testing is recommended to identify actionable oncogenic driver alterations in patients with Radioiodine-Refractory Differentiated Thyroid Cancer (RAIR DTC) before starting systemic therapy for progressive disease.
  • Multikinase Inhibitors (MKI)
    • The new guidelines strengthened recommendations for the use of MKI therapy for patients with RAIR DTC without an actionable biomarker-linked. Recommended first-line MKI treatments are lenvatinib or sorafenib.
    • Patients with symptomatic RAIR DTC who cannot get local therapy should start lenvatinib or other therapy without delay. 
    • Cabozantinib may be offered as a second-line treatment to patients with RAIR DTC without an actionable oncogenic driver alteration who get worse or cannot tolerate their initial MKI. 
  • Oncogenic Driver Alterations
    • There are new treatment recommendations for patients with actionable oncogenic driver alterations.
    • Patients with progressive RAIR DTC who have the following actionable oncogenic driver alteration should be given targeted treatment for their specific alteration as a first-line therapy
      • NTRK fusion
      • RET fusion
      • ALK fusion.
    • Patients with progressive RAIR DTC who have an oncogenic BRAF V600E mutation may consider BRAF V600E directed therapy as a first-line treatment if they are not candidates for lenvatinib.
    • Patients with a BRAF V600E mutation who have gotten worse or did not tolerate one or more MKI should be treated with BRAF-directed therapy.
    • BRAF-directed therapies are not recommended for patients with DTC who have non-V600 BRAF alterations.
    • Enrollment in a clinical trial or first-line lenvatinib is suggested for patients with progressive RAIR DTC who have other potential actionable targets.
  • Immunotherapy
    • There is a new recommendation that immunotherapy, including immune checkpoint inhibitors may be offered to select patients.
  • Cytotoxic Chemotherapy
    • Cytotoxic chemotherapy agents continue to be offered to patients with RAIR DTC as a treatment of last resort, preferably within a therapeutic clinical trial.

Comparison of Recommendations
Topic20152025

Genetic and Molecular Testing		Screening people with familial follicular cell–derived DTC may lead to an earlier diagnosis of thyroid cancer, but the panel cannot recommend for or against US screening since there is no evidence that this would lead to reduced morbidity or mortality.Germline genetic testing may be offered in the following scenarios:

• Clinical suspicion for Cowden/PTEN Hamartoma Tumor syndrome due to a combination of DTC and non-thyroid malignancy/tumors/features.

• In patients who were diagnosed with FNMTC as children, clinical and family history should be evaluated for features of DICER1 tumor predisposition. Consideration may be given to germline DICER1 testing in patients from families with pediatric patients with DTC.

• Pathologic diagnosis of cribriform morular thyroid carcinoma (APC gene).

• Other combinations of tumors and/or cancers in a patient and/or their family members may raise concern for a hereditary predisposition condition, including rare conditions such as Carney complex or Werner syndrome. In these patients, genetic counseling and testing may be offered.
There is a lack of evidence to suggest the utility of clinical germline genetic testing in non-syndromic FNMTC. In non-syndromic FNMTC, the non-thyroid malignancies in the family may drive decision-making regarding genetic testing.
Histopathologic variants associated with familial syndromes (cribriform-morular variant of papillary carcinoma often associated with FAP, follicular or papillary carcinoma associated with PTEN-hamartoma tumor syndrome) should be identified during histopathologic examination and reported.Individuals with a family history of FNMTC should have a careful history and directed neck examination as a part of regular health maintenance. Ultrasound screening may be considered in first-degree family members of individuals who meet criteria for a clinical diagnosis of FNMTC due to the presence of three or more (first or second degree) related individuals with diagnoses of non-medullary thyroid cancer (NMTC). 

Ultrasound screening may also be considered in families with only two affected individuals showing other concerning features (such as particularly young ages of diagnosis) or with limited family structure. The age for initiation of such screening requires further study and should be carefully weighed against the risk of overtreatment.
After consideration of clinical and sonographic features, mutational testing for BRAF or the seven-gene mutation marker panel (BRAF, RAS, RET/PTC, PAX8/PPARγ) may be considered in nodules with suspicion for papillary carcinoma (SUSP) cytology if such data would be expected to alter surgical decision-making.When genomic testing is performed on tumor samples for clinical purposes, both somatic and germline genetic alterations can be detected. If a potentially clinically relevant germline cancer-predisposing variant is detected, evaluate patients and their family histories for clinical correlation, and consider referral for genetic counseling for possible germline testing.
Genomic evaluation of confirmed DTC prior to surgery is not recommended routinely. However, if the genomic profile is known or performed, the presence or absence of specific combinations of abnormalities may be considered in the context of clinical, radiographic, and cytopathologic data to inform the extent of surgery.
The role of molecular testing in guiding postoperative RAI use has yet to be established; therefore, no molecular testing to guide postoperative RAI use can be recommended at this time.Tissue-based biomarker testing to identify actionable oncogenic driver alterations in RAIR DTC should be performed prior to initiating systemic therapy for progressive disease.
Targeted Therapy: Multikinase InhibitorsKinase inhibitor therapy should be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not otherwise amenable to local control using other approaches. Kinase inhibitors that are FDA approved for differentiated thyroid carcinoma or other available kinase inhibitors (preferably within the context of therapeutic clinical trials) can be considered since the impact of these agents on overall survival and quality of life remains to be defined.

Patients who are candidates for kinase inhibitor therapy should be thoroughly counseled on the potential risks and benefits of this therapy as well as alternative therapeutic approaches including best supportive care. Appropriate informed consent should be obtained and documented in the medical record prior to initiation of any therapy, regardless of whether the patient is being treated in the context of a clinical trial.		For patients with progressive RAIR DTC without an actionable biomarker-linked FDA- approved first-line therapy, multikinase inhibitor (MKI) therapy with either lenvatinib or sorafenib is recommended. In most cases, lenvatinib is the preferred first-line MKI.
Lenvatinib or other therapy should be initiated without delay in patients with symptomatic RAIR DTC for whom local therapy, such as radiation or surgery, is not appropriate. 

For patients with asymptomatic RAIR DTC that has progressed over the prior 12 to 14 months and local therapy is not appropriate, if efficacy outcomes are the most important goal of treatment, earlier initiation of lenvatinib may be considered. For patients with asymptomatic progressive RAIR DTC for whom quality of life is a major priority, delaying the initiation of lenvatinib and continuing disease monitoring may be most appropriate.
Patients who have disease progression while on initial kinase inhibitor therapy without prohibitive adverse effects should be considered for second-line kinase inhibitor therapy. Ideally, such therapy should be undertaken within the context of therapeutic clinical trials.Cabozantinib should be offered as second-line therapy for patients with RAIR DTC without an actionable oncogenic driver alteration who have progressed on or did not tolerate prior MKI therapy, if they desire ongoing treatment, and do not have a contraindication to therapy.
Other Targeted TherapiesIn patients with progressive RAIR DTC harboring an oncogenic NTRK fusion, NTRK- targeted therapy is recommended in the first line.
In patients with progressive RAIR DTC harboring an oncogenic RET fusion, RET-targeted therapy is recommended in the first line.
In patients with progressive RAIR DTC harboring an oncogenic ALK fusion, ALK-targeted therapy is recommended in the first line.
In patients with progressive RAIR DTC harboring an oncogenic BRAF V600E mutation, BRAF V600E-directed therapy may be considered in the first line for patients who are poor candidates for lenvatinib.

BRAF-directed treatment is recommended in patients with BRAF V600E mutation- positive RAIR DTC who have progressed on or did not tolerate one or more prior MKI therapies.

Currently approved BRAF-directed therapies are not recommended in DTCs harboring non-V600 BRAF alterations.
In patients with progressive RAIR DTC harboring other potentially actionable non- NTRK/RET/ALK/BRAF V600E targets, enrollment in a clinical trial or first-line lenvatinib is suggested.
ImmunotherapyNot AddressedImmune checkpoint inhibitors. or other forms of immunotherapy may be offered in selected cases, such as when tumors harbor a high tumor mutational burden or are mismatch repair-deficient.
Cytotoxic ChemotherapyCytotoxic chemotherapy can be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not otherwise amenable to control through other approaches, including kinase inhibitors. Too few data exist to recommend specific cytotoxic regimens, and use within the context of a therapeutic clinical trial is preferred.Cytotoxic chemotherapy can be considered in RAIR DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not amenable to control through other approaches. Use within the context of a therapeutic clinical trial is preferred.

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