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 progressed within months; BRAF/MEK inhibition and immunotherapy have started to change that.

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 (treatment)
• AL2846 (treatment)
• JK08 (treatment)
• 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 (treatment)
• Circulating tumour HPV DNA (ctHPV-DNA) (technology)
• Targeted alpha therapy (technology)

• LIBRETTO-531 (phase 3, n=291): Progression-free survival at 12 months: 86.8% vs 65.7%, HR 0.28
• 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%
• EXAM (phase 3, n=330): Progression-free survival: 11.2 months vs 4 months, HR 0.28
• ZETA (phase 3, n=331): Progression-free survival (independent central RECIST): Median follow-up 24 months; medians not reported in the abstract

• Overdiagnosis of microcarcinoma.
• Anaplastic thyroid cancer: BRAF V600E cases now respond to dabrafenib-trametinib, often enough to allow surgery; the 60% without the mutation still have few options.
• 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
• Wikipedia: https://en.wikipedia.org/wiki/Thyroid_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470