Predicting Response to Therapy: The Updated ATA Risk-Stratification System

• Unlike many cancers, the risk of recurrence does not parallel the risk of mortality in differentiated thyroid cancer
• In most patients, the risk of recurrence far exceeds the risk of disease-specific mortality:
  • Thus staging systems designed to predict mortality in thyroid cancer:
    • Would not be anticipated to be predictive of disease recurrence
• To address this issue, a risk-stratification system:
  • Was developed and validated to predict the risk of structural disease recurrence:
    • Based on information obtained around the time of initial therapy
  • A modified version of this original risk-stratification system was endorsed in the 2009 ATA guidelines and subsequently modified in the 2015 ATA guidelines
• Whereas initially conceived as a three-category model of risk assessment:
  • Low, intermediate, or high risk
• The ATA risk-stratification system:
  • Is now visualized as a continuum of risk:
    • Ranging from very low to very high risk of structural disease recurrence

• The three-category model was proven to be very useful and reproducible across multiple studies
• The 2015 ATA guideline:
  • Expanded the low-risk category to include not only intra-thyroidal papillary thyroid cancer but also patients with:
    • Very small-volume lymph node micro-metastases:
      • Less than 0.2 cm in largest dimension
    • Intra-thyroidal well-differentiated follicular thyroid cancer:
      • With capsular invasion and fewer than four foci of vascular invasion
    • Intra-thyroidal encapsulated follicular variant of papillary thyroid carcinoma:
      • Now known as noninvasive follicular thyroid neoplasm with papillary-like nuclear features
    • Either unifocal or multifocal intra-thyroidal papillary micro-carcinoma:
      • Even if they have known BRAF^V600E mutations
  • The high-risk category was also expanded to include:
    • Follicular cancer with more than four foci of vascular invasion and
    • Pathologic lymph node metastasis:
      • With any metastatic lymph node ≥ 3 cm in largest dimension
  • The remaining tumors were classified as intermediate risk based on the data available at the time the guidelines were written

• The last several years have seen an abundance of published data confirming the association among specific molecular alterations, histological subtypes, and clinical outcomes in follicular cell-derived thyroid cancer
  • Point mutations in BRAF^V600E:
    • Are associated with:
      • Increased risk of recurrence
      • Radioactive iodine refractoriness
      • Extrathyroidal extension
      • Lymph node metastases
      • Disease-specific mortality
  • Likewise, oncogenic genetic alterations in TERT promoter, TP53, EIF1AX, and β-catenin:
    • Are associated with more aggressive tumor behavior and poorer clinical outcomes
  • Furthermore, mutational combinations (such as BRAF^V600E + TERT promoter mutations or RAS + TERT promoter mutations):
    • Are associated with significantly increased risk beyond that associated with either mutation in isolation
  • As shown in the ATA continuum of risk figure:
    • Appropriate molecular risk stratification requires integration of the genetic abnormality into the proper clinical context:
      • As the presence of a specific mutation does not always portend a poor prognosis:
        • e.g., BRAF^V600E mutations are found in > 50% of papillary micro-carcinomas:
          • Which usually display an indolent clinical course
    • Although not yet proven:
      • It seems reasonable to consider either:
        • More careful follow-up or potentially more aggressive therapies for tumors with the highest risk mutational profiles:
          • Particularly those with mutational combinations associated with the poorest clinical outcome
    • It is important to remember that there is no guarantee that more aggressive surgery, radioactive iodine therapy, thyroid-stimulating hormone suppression, or other systemic therapies:
      • Will necessarily provide therapeutic benefit simply because we can identify a patient at high risk for poorer outcomes on the basis of clinic-pathological presentation or molecular profiling
    • Prospective studies evaluating the impact of more aggressive surgical and systemic therapies in the setting of high-risk mutational profiles are needed
• The ATA risk-stratification system performs well in clinical practice:
  • With low-risk patients:
    • Demonstrating no evidence of disease 80% to 90% of the time
    • Biochemical incomplete responses 15% of the time
    • Structural incomplete responses 3% to 5% of the time
  • Intermediate-risk patients achieve:
    • Excellent response ∼60% of the time
    • Have a biochemical incomplete response ∼15% to 20% of the time,
    • Structural incomplete response ∼20% of the time
  • High-risk patients achieve:
    • No evidence of disease status in less than 30% of the cases
    • Structural incomplete response 50% to 75% of the cases
    • Biochemical incomplete response 10% to 15% of the cases
  • The studies contributing to these approximations are extensively reviewed in the ATA guidelines
  • Interestingly:
    • Age is a major determinant of response to therapy:
      • In ATA high-risk patients:
        • The proportion of excellent responders was found to be significantly higher among younger patients (age < 55 years) than among older patients (age ≥ 55 years; 40.3% vs 27.5%, P = 0.02)
        • The proportion of structural incomplete responders was significantly larger among older patients than among younger patients (53% vs 33%, P = 0.002)
        • Moreover, ATA high-risk younger patients with a structural incomplete response to therapy had a significantly better DSS than older patients (74% vs 12%, respectively, P < 0.001)

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