Teaching pack: Thyroid cancer

Thyroid cancer is really several diseases. Differentiated thyroid cancer (papillary ~85%, follicular, oncocytic) arises from follicular cells, retains iodine uptake, and has a 10-year survival above 95%; its incidence has tripled in many countries because ultrasound finds tiny tumours that would never have caused harm. Medullary thyroid cancer comes from calcitonin-producing C cells, is driven by RET mutations (hereditary in MEN2), and does not take up iodine. Anaplastic thyroid cancer is rare, dedifferentiated, and historically fatal within months.

Differentiated disease is treated by surgery, with radioactive iodine (the first theranostic, 1946) reserved for intermediate and high-risk patients after HiLo, ESTIMABL2, and IoN showed low-risk patients gain nothing from it; active surveillance is accepted for microcarcinomas, and lobectomy suffices for many. When cancer becomes radioiodine-refractory, lenvatinib (SELECT) and sorafenib (DECISION) extend progression-free survival, and genotype directs selective therapy: selpercatinib for RET fusions, larotrectinib for NTRK, dabrafenib-trametinib for BRAF. Medullary cancer moved from vandetanib and cabozantinib to RET-selective selpercatinib after LIBRETTO-531 (2023). Anaplastic cancer with BRAF V600E responds to dabrafenib-trametinib (ROAR), often enabling surgery, and triplets with pembrolizumab are producing multi-year survivors.

• Genotype-directed therapy for aggressive subtypes.
• De-escalation is the story: radioiodine omitted for low-risk disease (ESTIMABL2, IoN), low-dose ablation when needed (HiLo), lobectomy and active surveillance for small tumours.
• Genotype-directed therapy covers most aggressive disease: RET (selpercatinib beat multikinase inhibitors head to head), BRAF, NTRK, ALK.
• Anaplastic thyroid cancer with BRAF V600E has moved from a median survival under six months to 15 months with the doublet and longer with immunotherapy added, and neoadjuvant use enables surgery.
• Molecular classifiers on needle biopsies have halved diagnostic surgery for indeterminate nodules.
• Redifferentiation with MAPK inhibitors can restore radioiodine uptake in about half of refractory patients.

1. 1946Radioactive iodine: first theranostic
2. 1946First patient treated with radioactive iodine for metastatic thyroid cancer
3. 1985RET proto-oncogene identified; MEN2 germline RET mutations follow (1993)
4. 2003BRAF V600E found in ~45% of papillary thyroid cancers
5. 2009Bethesda System for thyroid cytology standardises nodule reporting
6. 2011Vandetanib: first drug for medullary thyroid cancer
7. 2012HiLo and ESTIMABL1: low-dose radioiodine ablation is enough
8. 2013Sorafenib approved for RAI-refractory disease (DECISION); selumetinib redifferentiation proof of concept
9. 2015Lenvatinib approved (SELECT); ATA guidelines endorse active surveillance and less radioiodine
10. 2018Dabrafenib-trametinib approved for BRAF V600E anaplastic thyroid cancer (ROAR); larotrectinib tumour-agnostic

• Selpercatinib (product)
• BRAF/MEK plus PD-1 blockade as standard for BRAF-mutant anaplastic thyroid cancer (idea)
• BRAF/MEK inhibition → surgery in anaplastic thyroid cancer (pairing)
• MAPK inhibitor redifferentiation → radioiodine (pairing)
• Ultrasound restraint and surveillance to reverse thyroid cancer overdiagnosis (idea)
• Thyroid nodule FNA, Bethesda cytology & molecular classifiers (technology)
• Active surveillance of papillary microcarcinoma (technology)
• Pembrolizumab (product)
• Circulating tumour HPV DNA (ctHPV-DNA) (technology)
• Targeted alpha therapy (technology)
• MRD / molecular residual disease testing (technology)
• Dermoscopy, total-body photography & AI skin analysis (technology)

• LIBRETTO-531 (phase 3, n=291): Progression-free survival at 12 months: 86.8% vs 65.7%, HR 0.28
• IoN (phase 3, n=504): Recurrence-free at 5 years: 98% vs 96%
• DECISION (phase 3, n=417): Progression-free survival: 10.8 months vs 5.8 months, HR 0.59
• SELECT (phase 3, n=392): Progression-free survival: 18.3 months vs 3.6 months, HR 0.21
• ESTIMABL2 (phase 3, n=776): Patients without events at 3 years: 95.6% vs 95.9%
• HiLo (phase 3, n=438): Successful ablation: 85% vs 88.9%

• Overdiagnosis of microcarcinoma.
• Anaplastic thyroid cancer remains lethal.
• Overdiagnosis: incidence has tripled with no change in mortality; most detected cancers would never have caused harm, yet surveillance uptake outside Japan and Korea remains low.
• Anaplastic thyroid cancer without BRAF V600E (about 60%) still has a median survival of a few months.
• Resistance to RET-selective inhibitors via solvent-front (G810) mutations has no approved next-generation drug.
• Multikinase inhibitors for RAI-refractory disease cause hypertension, weight loss, and fatigue; most patients need dose reductions and quality of life suffers.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
3. Why might an alpha-emitting PSMA drug work after lutetium PSMA has stopped working?
   Answer

   Alpha particles (actinium-225) deposit far more energy over 50-100 µm, causing clustered double-strand breaks independent of oxygen and cell cycle, so beta-resistant, hypoxic, or small-volume disease can still be killed; retrospective series show PSA responses in about half after 177Lu failure. Supply of Ac-225 and salivary toxicity are the limits.
4. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
5. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).
6. What is a liquid biopsy used for in cancer care today?
   Answer

   A blood test reading tumour DNA fragments: to genotype a tumour when tissue is scarce, to track resistance mutations (EGFR T790M, ESR1), to detect minimal residual disease after surgery, and, experimentally, to screen for cancer.

• Wikipedia: https://en.wikipedia.org/wiki/Thyroid_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470