What does a BRAF (B-Raf proto-oncogene) V600E mutation indicate in thyroid cancer?

BRAF V600E Mutation in Thyroid Cancer: Clinical Significance and Implications

The BRAF V600E mutation in thyroid cancer indicates more aggressive disease behavior with higher risk of recurrence, lymph node metastasis, and extrathyroidal extension, particularly in papillary thyroid carcinoma (PTC). 1, 2

Prevalence and Tumor Association

• BRAF V600E is the most common genetic alteration in thyroid cancer, occurring in:

  • 45-50% of papillary thyroid cancers (PTC) overall 2
  • 51% of conventional/classical PTC 2
  • 24% of follicular variant PTC 2, 3
  • Rarely in follicular thyroid cancer (1.4%) 3
  • Some anaplastic thyroid cancers (which often derive from PTC) 2, 4

• The mutation is more common in aggressive histologic variants including:

  • Tall cell variant
  • Columnar cell variant
  • Solid variant
  • Hobnail variant 2

Clinical and Prognostic Implications

Risk Stratification

BRAF V600E mutation affects risk stratification in thyroid cancer:

• Intermediate Risk (6-20% recurrence risk) 1:

  • Intrathyroidal tumors <4cm with BRAF V600E mutation (10% recurrence risk)
  • Multifocal papillary microcarcinoma with extrathyroidal extension and BRAF V600E (20% recurrence risk)

• High Risk (>40% recurrence risk) 1:

  • Concomitant BRAF V600E and TERT promoter mutations act synergistically to dramatically increase recurrence risk

Associated Aggressive Features

BRAF V600E mutation is associated with 2, 5, 3, 6:

• Older patient age (≥45 years)
• Lymph node metastasis
• Extrathyroidal extension
• Distant metastasis
• Higher TNM stage
• Aggressive histologic features
• Infiltrative tumor borders (vs. well-circumscribed)
• Tumor-associated stromal desmoplasia/fibrosis
• Classic nuclear features of PTC

Therapeutic Implications

For advanced, progressive, or metastatic BRAF V600E-mutated thyroid cancer:

• BRAF inhibitors are effective treatment options 1:

  • Vemurafenib: Phase II trial showed 38.5% response rate in BRAF V600E-positive papillary thyroid cancer that was refractory to radioactive iodine 1, 7
  • Dabrafenib: Shows partial responses in 29% of patients with BRAF V600E-mutant thyroid carcinoma 1
  • Dabrafenib may also sensitize tumors to radioactive iodine therapy 1

• Molecular testing is recommended for patients with:

  • Advanced, progressive, or threatening differentiated thyroid cancer 1
  • Anaplastic thyroid cancer considering systemic therapy 1

• Treatment resistance: Patients may develop acquired resistance to BRAF inhibitors through secondary mutations, such as RAS mutations 4

Clinical Management Considerations

1. Diagnostic approach:

   • Consider BRAF V600E testing in patients with PTC, especially with aggressive histologic features
   • Testing is particularly important for advanced disease to guide therapy options

2. Risk assessment:

   • BRAF V600E status should be incorporated into risk stratification
   • Highest risk when combined with TERT promoter mutations

3. Treatment planning:

   • For localized disease: More aggressive surgical approach may be warranted
   • For advanced/metastatic disease: Consider BRAF inhibitor therapy

4. Surveillance:

   • Closer follow-up monitoring for patients with BRAF V600E-positive tumors
   • More vigilant surveillance for recurrence and metastasis

Pitfalls and Caveats

• BRAF V600E alone may not be sufficient to predict aggressive behavior; its relative contribution to recurrence risk is not well-defined 1
• Testing for additional mutations (especially TERT) provides more complete risk assessment
• Response to BRAF inhibitors is not universal, and resistance eventually develops in most cases 4
• The presence of BRAF V600E in microcarcinomas may still indicate aggressive potential, even in small tumors 5