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
As described in the ATA guidelines, individualized risk stratification is best visualized as a “continuum of risk” rather than as three discrete risk categories that predict the risk of structural disease recurrence. [Adapted with permission from Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1–133.]
  • 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 BRAFV600E 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 2015 ATA guidelines expanded the inclusion criteria for ATA low-risk and ATA high-risk disease categories as described in this table. [Adapted with permission from Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1–133.]
  • 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 BRAFV600E:
      • Are associated with:
        • Increased risk of recurrence
        • Radioactive iodine refractoriness
        • Extrathyroidal extension
        • Lymph node metastases
        • Disease-specific mortality
    • Likewise, oncogenic genetic alterations in TERT promoterTP53EIF1AX, and β-catenin:
      • Are associated with more aggressive tumor behavior and poorer clinical outcomes
    • Furthermore, mutational combinations (such as BRAFV600E + 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.BRAFV600E 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)

#Arrangoiz #ThyroidSurgeon #ThyroidExpert #ThyroidCancer #EndocrineSurgery #HeadandNeckSurgery #CancerSurgeon #SurgicalOncologist

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