Podcast Summary: Endocrine Feedback Loop

Episode: EFL053 – The Cost Effectiveness of Molecular Testing for Indeterminate Thyroid Nodules

Host: Chase Hendrickson, MD (Vanderbilt University)
Guests: Anupam Kotwal, MD (University of Nebraska Medical Center), Sarah Mason, MD (University of Colorado)
Date: September 19, 2024

Main Theme

This episode explores a recently published study on the use and cost-effectiveness of molecular testing (specifically ThyroSeq v3) for indeterminate thyroid nodules in Canada's publicly funded healthcare system. The panel discusses the evolution of managing indeterminate thyroid nodules, practical and financial implications of molecular diagnostics, and offers clinical insight and analysis on implementation and future directions.

Key Discussion Points & Insights

1. Background: Indeterminate Thyroid Nodules

Timestamps: 02:37–06:52

• Bethesda Cytology Categories:
  • ~20–30% of thyroid FNA biopsies yield indeterminate results (Bethesda III [AUS] or IV [follicular neoplasm])
  • Malignancy risks: 6–20% for Bethesda III; 14–35% for Bethesda IV, depending on prevalence and experience
• Typical Management Options:
  • Repeat FNA, especially for Bethesda III (up to half will get benign result)
  • Upfront surgery (hemithyroidectomy) for higher suspicion or patient preference
  • Consider surgery for Bethesda IV since repeat FNA is less informative
• Practical Challenges:
  • Patient logistics often necessitate reflexive molecular testing to avoid requiring repeat biopsies (esp. for patients drawn from large, remote regions)
  • Most diagnostic surgeries done for indeterminate nodules result in benign findings (up to 75%), exposing patients to unnecessary risks and increasing healthcare/surgical waitlists

“Ultimately being able to better preoperatively stratify nodules and the risk of malignancy using testing such as molecular testing is quite appealing.”
—Sarah Mason [09:09]

2. Role of Molecular Testing

Timestamps: 06:52–11:06

• Main Commercial Tests in US:
  • ThyroSeq v3: Next-gen sequencing, >112 genes, detects ~12,000 variants.
  • Afirma GSC: Gene expression classifier, mRNA signatures of 167 genes.
• Clinical Impact: Both aim to clarify malignancy risk and reduce unnecessary surgeries by distinguishing nodules more accurately than cytology alone.
• Evolution: Molecular testing has shifted the paradigm from "diagnose by surgery" to more selective surgery based on individualized risk.

“Molecular tests have been kind of like a game changer, especially in this indeterminate nodule to guide management, especially preventing unnecessary surgery.”
—Anupam Kotwal [36:17]

3. Study Design and Methodology

Host/Panel Explains Methods: 11:06–18:37

• Type: Cross-sectional, prospective study (500 patients with Bethesda III or IV indeterminate nodules, Quebec, Nov 2021–Nov 2022)
• Key Exclusions: Nodules >4cm, high-risk ultrasound (TIRADS 5), other indications for surgery, age <18
• Testing/Follow-up:
  • All patients underwent ThyroSeq v3; nodules with negative results monitored for 2 years (note: follow-up outcomes projected from literature)
  • NIFTP (Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features) classified as positive, reflecting management similarity to malignancy
• Primary Outcomes:
  • Benign call rate (proportion of nodules called benign via molecular testing and managed non-surgically)
  • Cost benefit: Financial impact vs. standard diagnostic surgery

“Negative predictive value...cannot actually be determined. And that's because most of those patients who have negative molecular testing don't go to surgery. Therefore, we can't calculate true negative rates or false negative rates...”
—Sarah Mason [18:38]

4. Key Study Results

Timestamps: 20:16–24:16

• Benign Call Rate: 72.6% overall (78% for Bethesda III; 65% for Bethesda IV)
• Management Outcomes:
  • 99.7% of molecular test negative patients did not undergo surgery; only 1 underwent surgery (benign result)
  • Positive molecular tests: 94% proceeded to surgery; among them, 67.6% were malignant or NIFTP
  • 32% of operated, test-positive cases were ultimately benign—RAS mutations were most common in this group
• Cost Savings:
  • Using the study’s parameters, molecular testing saved $860,000 annually over 3 years (projected $8.6 million over 10 years)
  • Even with test costs rising to $6,000 per case, molecular testing would still be cost-saving compared to routine surgery

5. Discussion and Practical Interpretation

Timestamps: 24:16–30:00

• Clinical Utility:
  • High benign call rate allows most (72.6%) patients with indeterminate nodules to avoid unnecessary surgery
  • Consistency with US studies reinforces the value of molecular testing, though generalizability depends on population prevalence, healthcare system, and patient selection
• Comparison Across Tests:
  • “No differences” seen between ThyroSeq v3 and Afirma GSC performance in recent head-to-head studies [26:30]
• Future Directions:
  • Active surveillance for certain low-risk positive molecular findings is gaining interest, with genomic data helping tailor management
  • BRAF V600E is still nearly always malignant, so typically warrants surgery; low-risk mutations plus comorbidities may tip toward observation
• Study Limitations:
  • No surgical pathology for most molecular test-negative nodules (cannot prove all were truly benign)
  • Missing surgical follow-up for some test-positive cases
  • Short follow-up period (2 years for benign test group; thyroid cancers often indolent—longer-term data crucial)
  • Cost estimates depend on local prices and indirect factors

Notable Quotes & Memorable Moments

• On the future of molecular testing:

  “I do think that could be the future and where we're going, but just a lot more research is needed...The majority of currently available research demonstrates that…the specific genetic alteration that's identified on molecular testing doesn't seem to be an independent predictor [of tumor aggression].”
  —Sarah Mason [38:41]

• On current clinical application:

  “This confirms, I think, what current practice is in the United States...they were able to demonstrate cost effectiveness...in a public health care system where generally the cost of healthcare is lower than in countries like the United States.”
  —Sarah Mason [36:42]

• On avoiding surgery:

  “Molecular testing, when benign, can really help patients that we serve in terms of preventing them from undergoing some of these interventions that are a little more invasive.”
  —Sarah Mason [37:34]

• On study design:

  “So, yeah, I think there's some good takeaway points from this study in that the test still showed a good performance in terms of preventing surgeries just to diagnose the nodules, and that these tests have performed very well...in pretty much all settings.”
  —Anupam Kotwal [34:10]

Timestamps for Important Segments

• Background and clinical challenge: 02:37–06:52
• Evolution of management & molecular testing: 06:52–11:06
• Methodology overview & design strengths/limitations: 11:06–18:37
• Interpretation of NIFTP’s role in molecular testing: 15:12–16:52
• Results summary—benign call rate & cost analysis: 20:16–24:16
• Affirma vs. ThyroSeq: Test comparison: 26:30–27:14
• Limitations & generalizability: 29:44–33:15
• Practice impact and application: 34:09–37:34
• Future predictions for molecular diagnostics: 38:41–40:01

Clinical Practice Implications

• Molecular testing now strongly supports avoiding unnecessary thyroid surgery in patients with indeterminate cytology, provided proper risk stratification by ultrasound and clinical context.
• The clinical applicability depends on local disease prevalence, available molecular platforms, and health economics.
• Multidisciplinary collaboration and nuanced understanding of test performance are key—particularly regarding specific genetic results and patient context (e.g., comorbidities, nodule appearance, patient preference).

Panel’s Closing Thoughts

Anupam Kotwal:
Molecular tests have become a clinical game-changer but should be used thoughtfully, considering local malignancy rates, ultrasound risk, and patient features. Test limitations include some false positives in oncocytic nodules and the need for refinement/improvement.

Sarah Mason:
This study affirms current US practice, demonstrates cost-effectiveness—even in cost-contained systems—and supports molecular testing’s value in sparing many patients unwanted surgery. However, both longer follow-up and more granular risk stratification (especially for aggressiveness) remain areas for future research and refinement.

Summary Table

| Segment | Start | Key Points | |-------------------------------------------|------------|-----------------------------------------------------------------| | Background/Clinical Problem | 02:37 | Indeterminate nodules: prevalence, risks, current management | | Role & Impact of Molecular Testing | 06:52 | Molecular platforms, clinical evolution, US practice | | Study Design/Methods | 11:06 | Design, inclusion/exclusion, rationale for outcome metrics | | NIFTP Classification | 15:12 | Borderline, treated as positive due to management similarity | | Study Results (Clinical & Economic) | 20:16 | Benign call rates, surgeries avoided, cost savings calculated | | Generalizability, Practice Application | 26:30 | Comparisons, test selection, population differences | | Limitations & Future Directions | 29:44 | Follow-up, missing data, economic assumptions, risk stratifying | | Clinical Practice/Future of Testing | 34:09 | Real world guidance, test utility, outlook for molecular testing|

Bottom Line:
Molecular testing for indeterminate thyroid nodules—when applied in a well-selected population—can safely avoid unnecessary surgery and deliver substantial cost savings, even in a single-payer healthcare context. Continued research will further refine risk stratification, pursue active surveillance models, and may eventually support mutation-specific guidance on cancer aggressiveness and long-term management.