A Patient's Guide to RET-Targeted Treatment for Thyroid Cancer — What the Latest Research Means for You

Table of Contents

• Key Points
• Background: Why This Research Matters
• What Is the RET Gene and What Does It Normally Do?
• How RET Drives Thyroid Tumors
• Hereditary Thyroid Cancer Syndromes: MEN2A and MEN2B
• Sporadic MTC and RET Fusions in Papillary Thyroid Cancer
• How Doctors Test for RET Alterations
• First-Generation Treatments: Multikinase Inhibitors
• Cabozantinib and the EXAM Trial
• Vandetanib and the ZETA Trial
• Why Multikinase Inhibitors Fall Short
• Selective RET Inhibitors: A More Precise Approach
• Comparing Drug Potency in the Laboratory
• Selpercatinib: Trial Results and Approval
• Pralsetinib: Trial Results and Approval
• Side-by-Side Efficacy Data
• Side Effects and Tolerability
• Resistance: Why These Drugs Stop Working
• What This Means for Patients
• Limitations of the Evidence
• Practical Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• Guidelines recommend germline RET testing for everyone with a new MTC diagnosis, because 1% to 7% of apparent sporadic cases are actually hereditary.
• In a phase III trial, first-line selpercatinib more than doubled 24-month progression-free survival versus cabozantinib or vandetanib (76.4% vs 37.2%).
• Selective RET inhibitors caused fewer treatment-stopping side effects than multikinase inhibitors: 5% vs 27% discontinuations in the phase III comparison.
• No RET inhibitor cures advanced RET-altered thyroid cancer; resistance mutations eventually emerge and the cancer progresses.
• Testing has limits: DNA-based NGS can miss fusions, liquid biopsies can be falsely negative, and immunohistochemistry is unreliable for screening.

Background: Why This Research Matters

The RET gene (short for "REarranged during Transfection") acts as an oncogenic driver — a gene change that pushes cells to become cancerous — in several cancers. The two most common are medullary thyroid cancer (MTC, a cancer of the thyroid's hormone-producing C cells) and papillary thyroid cancer (PTC, the most common type of thyroid cancer).

RET was first identified and cloned in 1985. For many years afterward, patients with advanced RET-altered tumors had few good options. That changed over the last two decades. Researchers learned the detailed shape of the RET kinase domain (the part of the protein that sends growth signals) and how it becomes overactive.

A key turning point came in 2012, when RET fusions were discovered in lung adenocarcinoma (a type of lung cancer). That discovery accelerated drug development. Since then, several non-specific multikinase inhibitors and RET-specific kinase inhibitors have shown real clinical benefit in RET-altered thyroid cancers.

Still, none of these drugs cure the disease. Response to treatment lasts a limited time, resistance eventually appears, and the cancer progresses. This review, published 30 years after germline RET mutations were first linked to the multiple endocrine neoplasia (MEN) type 2 syndromes, summarizes where treatment stands today and what comes next.

What Is the RET Gene and What Does It Normally Do?

RET is a transmembrane glycoprotein receptor tyrosine kinase, or RTK — a protein that sits in the cell membrane and relays growth signals into the cell. It plays an important role in maintaining normal neural, hematopoietic (blood-forming), and neuroendocrine tissues.

The receptor has two main parts. The extracellular domain (the portion outside the cell) contains four cadherin-like repeats, a calcium binding site, and a cysteine-rich domain. The intracellular domain (inside the cell) contains tyrosine kinase residues — the switches that trigger signaling.

RET works differently from most receptors. It does not bind its signaling molecule (ligand) directly. Instead, proteins called GDNF family ligands first attach to GFRα co-receptors. That combined complex then forces two RET molecules together, a process called homodimerization.

Once paired, RET adds phosphate groups to itself (trans-autophosphorylation) on tyrosine residues. This switches on signaling pathways involved in cell growth and survival, notably the MAPK and PI3K pathways. In cancer, this signaling becomes stuck in the "on" position.

Researchers have also described an indirect route to cancer. RET-mediated activation of the MAPK pathway can suppress major histocompatibility complex class I expression on cancer cells. That matters because MHC class I is essential for cytotoxic CD8+ T cells to recognize and attack tumor cells.

How RET Drives Thyroid Tumors

Oncogenic RET activation happens through three main mechanisms:

1. Mutations that cause ligand-independent dimerization — the receptor pairs up and switches on without any signal.
2. Mutations that directly and abnormally activate the kinase domain — the growth switch is permanently flipped.
3. Chromosomal rearrangements that create chimeric (fusion) proteins with a constantly active RET kinase domain.

All three lead to ligand-independent activation of downstream signaling, which ultimately promotes tumor formation.

Hereditary Thyroid Cancer Syndromes: MEN2A and MEN2B

About one quarter of MTC cases are hereditary. They arise from germline (inherited, present in every cell) gain-of-function mutations in the RET proto-oncogene and form part of the MEN2A and MEN2B syndromes.

MEN2A causes MTC in virtually all patients. Other features vary. Other features can include pheochromocytoma (a tumor of the adrenal gland). Other features can include primary hyperparathyroidism (overactive parathyroid glands). Other features can occasionally include cutaneous lichen amyloidosis (an itchy skin condition). Other features can occasionally include Hirschsprung disease (a bowel motility disorder). How severe the disease is depends on the specific genotype, both in terms of penetrance (how likely the condition is to appear) and how aggressive the MTC becomes.

Most germline mutations causing MEN2A sit in the extracellular cysteine-rich domain (CRD), most commonly at cysteine C634 in exon 11. These mutations create abnormal intermolecular disulfide bonds between free cysteine residues. That allows the receptors to pair up without a ligand and activates the RET kinase.

MEN2B is less common, accounting for only 5% of hereditary MTCs. However, MTC in these patients often appears in infancy and is highly aggressive. MEN2B is almost always caused by a germline RET M918T mutation in exon 16, which swaps the amino acid methionine for threonine inside the kinase domain. This increases ATP binding and autophosphorylation, allowing activation without dimerization. Fewer than 5% of MEN2B patients carry an A883F mutation in exon 15 or double mutations involving V804M.

Beyond MTC, MEN2B hallmarks include pheochromocytoma, generalized ganglioneuromatosis of the aerodigestive tract (nerve tissue overgrowth in the breathing and digestive passages), eye abnormalities, and skeletal malformations such as a marfanoid body habitus (unusually tall, thin build with long limbs).

Sporadic MTC and RET Fusions in Papillary Thyroid Cancer

RET mutations are also the hallmark of sporadic MTC (cancer with no inherited mutation), found in about 55% to 65% of cases. RET M918T is the most frequent somatic mutation (a mutation acquired during life, not inherited). Less common point mutations occur at residues C634, A883, and C630. Deletions and small insertions are occasionally reported as well.

PTC behaves differently. Here, RET fusions — not mutations — act as the oncogenic driver, particularly in children and after radiation exposure. RET fusions occur in 5% to 10% of PTCs. The most common partners are CCDC6-RET and NCOA4-RET, formed when a DNA double-strand break is repaired incorrectly.

Fusions activate downstream signaling in one of two ways. Either the partner gene contributes a dimerization domain that forces RET to pair up and activate without a ligand. Or the partner gene is expressed everywhere in the body, causing RET to be produced in cells where RET normally would not be.

How Doctors Test for RET Alterations

Testing matters because between 1% and 7% of patients who appear to have sporadic MTC actually have hereditary disease. For that reason, guideline experts recommend germline RET mutation testing for every patient with a new MTC diagnosis. When no germline mutation is found, testing for somatic RET alterations is recommended in advanced medullary and differentiated thyroid cancers when systemic therapy is being considered.

Several testing methods exist, and the best choice depends on what is being looked for and the quality and quantity of tissue available:

• Immunohistochemistry — unreliable for screening, because RET protein overproduction also occurs in benign (non-cancerous) lesions.
• Fluorescent in situ hybridization (FISH) — detects RET fusions with good sensitivity and specificity, but cannot identify the fusion partner, and success depends heavily on tissue quality.
• DNA quantitative PCR (Q-PCR) — screens for selected hotspot mutations, but is limited by the number of primers available and cannot detect fusions.
• RNA-based reverse transcription PCR (RT-PCR) — can detect fusions, but only known partners for which specific primers exist.
• Next-generation sequencing (NGS) — tests many gene alterations at once with relatively high sensitivity and specificity. DNA-based NGS detects mutations well even in samples with few tumor cells. But DNA-based NGS has limited sensitivity for fusions. DNA-based NGS gives no information on whether a rearranged RET gene is actually being transcribed into protein. This is partly because breakpoints can fall inside intron 11, and occasionally introns 7 and 10, which are large regions to cover.
• RNA-based NGS — more specific and sensitive for fusions because introns are spliced out of RNA, removing the coverage problem. It can also confirm whether the fusion is "in frame," meaning it produces a working protein. The trade-off is that RNA is fragile.
• Liquid biopsy (circulating cell-free DNA) — an option when no tumor tissue is available. It is very sensitive, but has biological and technical limitations, so a negative result should be confirmed with tumor tissue testing.

In 2021, the European Society of Medical Oncology (ESMO) issued recommendations. For MTC, start with germline testing using Q-PCR or NGS on blood or sputum. If a familial RET mutation is already known, DNA Sanger sequencing can be performed on circulating white blood cells. When no germline RET mutation is found, NGS on a formalin-fixed, paraffin-embedded (FFPE) tissue specimen is the test of choice. This test is for sporadic MTC and other cancers that can carry RET alterations.

First-Generation Treatments: Multikinase Inhibitors

Because RET is a tyrosine kinase receptor, its kinase domain resembles those of other tyrosine kinases. As a result, several multikinase inhibitors (MKIs) — drugs that block multiple targets at once — have anti-RET activity, though with varying strength.

Only two MKIs are currently approved by the US Food and Drug Administration (FDA) for advanced metastatic MTC, regardless of RET mutation status: cabozantinib and vandetanib. Lenvatinib, cabozantinib, and sorafenib are approved for advanced radioiodine-refractory differentiated thyroid carcinomas (RR-DTCs), meaning cancers that no longer respond to radioactive iodine — including those with RET alterations.

Cabozantinib and the EXAM Trial

Cabozantinib blocks MET (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor 2) in addition to RET. Both MET and VEGFR-2/VEGFR-3 are overactive in MTC and contribute to its growth, which is why the drug was studied in this cancer.

An early phase I study showed encouraging results, leading to a phase III placebo-controlled trial. The EXAM trial randomized 330 patients with progressive metastatic MTC in a 2:1 ratio to cabozantinib or placebo.

• Progression-free survival (PFS, time before the cancer worsened) was 11.2 months with cabozantinib versus 4.0 months with placebo (hazard ratio [HR] 0.28; 95% confidence interval [CI], 0.19–0.40; P<0.001).
• The PFS benefit appeared regardless of tumor burden, tumor location, prior TKI treatment, or RET mutation status.
• A planned interim analysis found no statistically significant difference in overall survival (OS, time until death from any cause) between the two groups (HR 0.98; 95% CI, 0.63–1.52).
• A survival subanalysis based on tumor genotype did find significant benefit in patients whose MTC carried the RET M918T mutation: 44.3 months versus 18.9 months with placebo (HR 0.60; 95% CI, 0.38–0.94; P=0.03).

Side effects reported in more than 40% of cabozantinib-treated patients were diarrhea, palmar-plantar erythrodysesthesia (hand-foot skin reaction), decreased weight and appetite, nausea, and fatigue. Grade 3 or 4 adverse events (serious enough to need medical attention) occurred in 69% of patients. The most frequent were diarrhea (16%), palmar-plantar erythrodysesthesia (13%), and fatigue (9%).

Because of its anti-angiogenic activity (its ability to block blood vessel growth), cabozantinib was also linked to hypertension (33%), hemorrhage or bleeding (25%), gastrointestinal perforation (3%), and fistula formation (5%).

Vandetanib and the ZETA Trial

Vandetanib blocks EGFR (epidermal growth factor receptor), VEGFR-2/3, and RET. Like cabozantinib, it counteracts excessive stimulation of blood vessel growth and growth pathways in MTC, but its anti-angiogenic effect is weaker than cabozantinib's.

Two phase II trials showed an acceptable toxicity profile and anti-tumor activity. That led to the phase III ZETA trial, which compared vandetanib with placebo in 333 patients with locally advanced or metastatic MTC, randomized 2:1. After a median follow-up of 24 months:

• PFS was significantly longer with vandetanib: 30.5 months versus 19.3 months (HR 0.46; 95% CI, 0.31–0.69; P<0.001).
• Objective response rate (ORR, the percentage of patients whose tumors shrank measurably) was significantly better: 45% versus 13% (P<0.001).
• Overall survival could not be properly assessed, because patients whose disease progressed on placebo were allowed to switch to vandetanib.

The most common side effects were diarrhea, rash, and nausea. Twenty-four percent of patients experienced grade 3 or higher events, including diarrhea (11%) and hypertension (9%). The most concerning side effect was QTc prolongation (an abnormal heart rhythm reading on an electrocardiogram), reported in 19 patients (8%). No cases of torsades de pointes (a dangerous heart rhythm) occurred.

An important design difference: patients did not need to have progressive disease to enter ZETA, whereas EXAM required progression within the previous 14 months. This raises the question of whether vandetanib's longer PFS partly reflected a less aggressive patient population. A post-hoc analysis of ZETA looked specifically at the 184 patients with progressive and symptomatic disease and found similar PFS benefits in that subgroup (HR 0.43; 95% CI, 0.28–0.64; P<0.0001).

Why Multikinase Inhibitors Fall Short

Despite their effectiveness, MKIs have serious drawbacks.

First, although they act on RET, their anti-VEGFR activity dominates at drug concentrations that can safely be achieved in patients. In practical terms, these drugs hit VEGFR-2 far more than they hit RET.

Second, anti-RET activity varies by mutation. Cabozantinib and vandetanib effectively inhibit RET M918T, but have limited activity against RET V804 gatekeeper mutations, with IC50 values 100 to 10,000 times higher than against normal (wild-type) RET. (IC50 is the concentration needed to inhibit growth by 50% in the laboratory — a lower number means a more potent drug.)

Third, off-target activity — especially against VEGFR — causes dose-limiting side effects that further reduce how well these drugs work.

Fourth, none of these agents produce complete responses, and their benefit is time-limited. Most patients eventually develop resistance and their disease progresses. Known resistance mechanisms include acquired RET V804L/M gatekeeper mutations, which block drugs from reaching the hydrophobic ATP-binding pocket of RET. Known resistance mechanisms also include S904F missense mutations, which increase the kinase's autophosphorylation activity.

Lenvatinib and sorafenib have also been studied in small groups of patients with advanced RET-mutated MTC, both with only modest efficacy.

For RET-altered RR-DTCs, none of the trials that led to approval of lenvatinib, cabozantinib, or sorafenib specifically examined the subgroup of patients with RET fusions. Nor did trials exploring sunitinib or vandetanib specifically examine the subgroup of patients with RET fusions. Extrapolating from RET-rearranged non-small cell lung cancer (NSCLC), MKIs produced limited PFS prolongation and lower response rates than targeted therapy does in NSCLC with ALK fusions or EGFR mutations. This suggests that off-target activity limits how well MKIs work in RET fusion-positive tumors compared with more specific drugs.

Selective RET Inhibitors: A More Precise Approach

To overcome these limitations, researchers developed two drugs with potent and highly selective anti-RET activity: selpercatinib and pralsetinib.

Selpercatinib, formerly known as LOXO-292, is an ATP-competitive, highly selective small-molecule inhibitor of RET-altered kinases. Laboratory studies showed potent anti-tumor activity in RET-altered mouse tumor models, high selectivity for RET, activity against V804 gatekeeper mutations, and some activity inside the brain (intracranial activity).

Pralsetinib, formerly known as BLU-667, was also designed as a potent, highly selective inhibitor of activating RET alterations. Laboratory studies showed subnanomolar potency (IC50 0.4 nmol/L) against common oncogenic RET alterations, including V804M/L gatekeeper mutations and various fusions. It is at least 100-fold more selective for RET than for other kinases, with limited VEGFR-2 inhibition.

Comparing Drug Potency in the Laboratory

The table below shows how much drug (in nanomoles per liter, nM) is needed to inhibit growth by 50% (the IC50). Lower numbers mean greater potency. Notice two patterns. Selective RET inhibitors need far lower concentrations than MKIs against RET alterations. Selective RET inhibitors need much higher concentrations to hit VEGFR-2, which explains their better side effect profiles.

Selpercatinib: Trial Results and Approval

The LIBRETTO-001 phase I/II trial confirmed selpercatinib's clinical efficacy in advanced RET-altered thyroid cancers. Updated results presented at the 2022 ESMO Congress included 142 patients who had never received an MKI and 151 patients previously treated with vandetanib and/or cabozantinib. Earlier results presented at the 2021 ASCO Annual Meeting also included 22 patients with RET fusion-positive thyroid cancers.

• Objective response rate: 81.0% (95% CI, 73.6–87.1) in treatment-naïve MTC
• Objective response rate: 73.5% (95% CI, 65.7–80.4) in previously treated MTC
• Objective response rate: 77.3% (95% CI, 54.6–92.2) in RET fusion-positive thyroid cancer
• Responses were durable: 84% and 65% were still ongoing at 2 years in treatment-naïve and previously treated MTC, respectively
• Median duration of response was 18.4 months in the RET fusion-positive group

The drug was well tolerated overall. Only 7% of patients (23 of 319) discontinued treatment because of drug-related side effects. The most frequent grade 3 or higher side effects were hypertension (22% of patients) and increased liver enzymes reflecting cell damage (alanine aminotransferase elevated in 8%, aspartate aminotransferase in 7%).

These efficacy and safety results led to FDA approval in 2020 for patients with RET fusion-positive differentiated thyroid cancers and RET-mutant MTC who require systemic therapy.

Then came the head-to-head evidence. The multicenter randomized phase III LIBRETTO-531 trial compared first-line selpercatinib with the physician's choice of cabozantinib or vandetanib in advanced, MKI-naïve, RET-mutant MTC. At 24 months, PFS was 76.4% (95% CI, 66.5–83.8) with selpercatinib versus 37.2% (95% CI, 21.9–52.6) with the MKIs (HR for disease progression or death, 0.28; 95% CI, 0.16–0.48; P<0.001). Selpercatinib was also better tolerated: 5% versus 27% of patients stopped treatment because of side effects, and 39% versus 77% needed dose reductions. This study established selpercatinib as the preferred first-line treatment for advanced and/or metastatic RET-mutant MTC and will influence drug approval and reimbursement decisions in many countries.

Pralsetinib: Trial Results and Approval

The phase I/II ARROW trial confirmed pralsetinib's clinical efficacy and favorable toxicity profile in locally advanced or metastatic RET-altered thyroid cancers, including 134 RET-mutant MTCs and 25 previously treated RET fusion-positive thyroid cancers.

In the intention-to-treat (ITT) MTC population, which counts every enrolled patient, updated results showed:

• Objective response rate 52.2% (95% CI, 39.7–64.6) in patients previously treated with cabozantinib and/or vandetanib (n=67)
• Objective response rate 71.6% (95% CI, 59.3–82.0) in treatment-naïve patients (n=67)

Among patients with previously treated RET fusion-positive thyroid cancer, ORR was 84.0% (95% CI, 63.9–95.5), including 4 complete responses (no detectable cancer) and 17 partial responses (tumor shrinkage).

Responses were durable. Median PFS was 25.8 months (95% CI, 19.7–35.0) in previously treated MTC and 25.4 months (95% CI, 17.0–not reached) in RET fusion-positive thyroid cancer. Median PFS was not reached in the treatment-naïve MTC group, but the 18-month PFS rate was 79.4% (95% CI, 69.4–89.5).

Pralsetinib was generally well tolerated. The most frequent grade 3 side effects were hypertension (17% of patients) and low blood cell counts — neutropenia (low neutrophils, 13%), lymphopenia (low lymphocytes, 11%), and anemia (low red blood cells, 10%). The most frequent serious treatment-related side effect was pneumonitis (lung inflammation), occurring in 5 patients (3%). One case of grade 5 (fatal) Pneumocystis jirovecii pneumonia occurred after 44 days on therapy. Rates of dose reduction and treatment discontinuation were low: only 10 of 175 patients (6%) stopped therapy because of drug toxicity.

Pralsetinib received FDA accelerated approval for advanced RET-altered thyroid cancers in 2020. However, the RET-mutant MTC indication was voluntarily withdrawn by the drug's sponsor at the end of June 2023.

Side-by-Side Efficacy Data

The table below organizes the key trial results described above. "Median follow-up" is how long, on average, patients were tracked. PFS figures are landmark rates — the percentage of patients still progression-free at that time point.

Side Effects and Tolerability

The shift from MKIs to selective RET inhibitors changed the side effect landscape substantially. To put the numbers in context: 69% of cabozantinib-treated patients had grade 3 or 4 side effects. And 27% of patients on cabozantinib or vandetanib stopped treatment because of side effects in the phase III comparison. With selpercatinib, that discontinuation rate was 5%.

That said, selective RET inhibitors are not side-effect free. The most common issues are:

• Hypertension — 22% grade 3 or higher with selpercatinib; 17% with pralsetinib
• Liver enzyme elevation — 8% (ALT) and 7% (AST) grade 3 or higher with selpercatinib
• Low blood counts — neutropenia 13%, lymphopenia 11%, anemia 10% with pralsetinib
• Pneumonitis (lung inflammation) — 3% with pralsetinib, including one fatal case of Pneumocystis jirovecii pneumonia after 44 days of treatment

Regular blood pressure monitoring, blood tests, and prompt reporting of new shortness of breath or cough are important parts of care on these drugs.

Resistance: Why These Drugs Stop Working

No RET inhibitor currently cures advanced RET-altered thyroid cancer. Response to therapy is limited in time, and progression eventually occurs.

Resistance comes in different forms. When patients progress on therapy, they can acquire new mutations that block the drug from binding to RET. Acquired RET V804L/M gatekeeper mutations interfere with drug access to the ATP-binding pocket. S904F missense mutations increase the kinase's autophosphorylation, driving resistance to cabozantinib and vandetanib.

The potency table above shows why this matters clinically. Pralsetinib and selpercatinib remain relatively active against V804L (IC50 of 1.8 and 17 nM) and V804M (17 and 56 nM), whereas vandetanib needs 3597 nM and 726 nM respectively. But against later mutations such as G810C and G810R, all four drugs require concentrations hundreds to thousands of times higher, meaning these mutations can defeat current therapies.

The review also highlights future therapeutic avenues, including the possibility of using RET inhibitors before surgery (neoadjuvant treatment) and developing next-generation agents that overcome resistance. This remains an active area of research.

What This Means for Patients

If you have advanced MTC or a RET fusion-positive thyroid cancer, RET testing is no longer optional — it directs treatment. Because 1% to 7% of apparently sporadic MTC cases are actually hereditary, everyone with a new MTC diagnosis should have germline testing. A positive result affects not only treatment but also screening for family members.

For advanced, MKI-naïve RET-mutant MTC, selpercatinib is now the preferred first-line treatment. This is based on phase III data showing 76.4% versus 37.2% PFS at 24 months, fewer treatment discontinuations (5% versus 27%), and fewer dose reductions (39% versus 77%).

For patients who have already received cabozantinib or vandetanib, selective RET inhibitors still produce meaningful responses: 73.5% response rate for selpercatinib in previously treated MTC and 52.2% for pralsetinib. For RET fusion-positive thyroid cancers, response rates were 77.3% to 84.0%.

Treatment selection must also account for current regulatory status. Selpercatinib holds full approval for RET fusion-positive DTCs and RET-mutant MTCs requiring systemic therapy. Pralsetinib's RET-mutant MTC indication was voluntarily withdrawn in June 2023, so availability may differ by country and indication.

Limitations of the Evidence

Understanding what the data can and cannot show helps patients make informed decisions.

• No cures. Every drug discussed is non-curative. Even with the best response rates, resistance eventually develops and the cancer progresses.
• Cross-trial comparisons are imperfect. Entry criteria differed between studies. ZETA did not require progressive disease, while EXAM required progression within 14 months, so comparing vandetanib's 30.5-month PFS with cabozantinib's 11.2-month PFS directly is misleading.
• Overall survival data are incomplete. In EXAM, the interim OS analysis showed no significant difference between arms (HR 0.98), though the RET M918T subgroup did show benefit (44.3 versus 18.9 months). In ZETA, OS could not be properly assessed because patients crossed over from placebo.
• Small cohorts for fusion-positive disease. The RET fusion-positive thyroid cancer groups in the selective inhibitor trials numbered only 22 and 25 patients, so estimates carry wide confidence intervals.
• No dedicated RET-fusion trials for older drugs. None of the registration trials for lenvatinib, cabozantinib, sorafenib, sunitinib, or vandetanib in differentiated thyroid cancer analyzed the RET fusion subgroup. So conclusions there rest on extrapolation from lung cancer data.
• Testing has blind spots. DNA-based NGS can miss fusions, liquid biopsies can produce false negatives, and immunohistochemistry is unreliable. A negative test on one platform does not always rule out a RET alteration.

Practical Recommendations

1. Ask for germline RET testing at diagnosis. Everyone with a new MTC diagnosis should be tested, because 1% to 7% of apparent sporadic cases are hereditary and results guide family screening.
2. Ensure somatic testing before systemic therapy. When advanced medullary or differentiated thyroid cancer treatment is being planned, tumor testing (ideally RNA-based NGS for fusions, or NGS on an FFPE specimen) should be performed.
3. Confirm a negative liquid biopsy with tissue testing. Cell-free DNA testing is sensitive but has technical limits.
4. Discuss selpercatinib as first-line therapy for advanced RET-mutant MTC if you have not previously received a multikinase inhibitor, based on the phase III LIBRETTO-531 results.
5. Plan for monitoring. Blood pressure checks, liver enzyme tests, and blood counts are needed on both selective RET inhibitors. Report new cough or shortness of breath promptly, because pneumonitis occurred in 3% of pralsetinib-treated patients.
6. Ask about clinical trials. Because resistance mutations such as G810C, G810R, and S904F can defeat current drugs, trials of next-generation inhibitors and of neoadjuvant (pre-surgery) approaches may offer additional options.

Frequently Asked Questions

I was just diagnosed with medullary thyroid cancer. Do I need genetic testing?

Yes. Guidelines recommend germline RET testing for everyone with a new MTC diagnosis, because 1% to 7% of patients who appear to have sporadic disease actually have an inherited mutation. A positive result guides your treatment and tells you whether family members should be tested too.

What does it mean if my tumor has a RET mutation?

A RET mutation is a gene change that can drive thyroid cancer growth. In medullary thyroid cancer, RET mutations are found in about 55% to 65% of sporadic cases and in inherited MEN2 syndromes. Knowing your RET status helps your doctor choose treatments that target this specific change.

What is the difference between a multikinase inhibitor and a selective RET inhibitor?

Multikinase inhibitors like cabozantinib and vandetanib block RET plus other proteins such as VEGFR, which causes more side effects. Selective RET inhibitors like selpercatinib and pralsetinib target RET far more precisely. In trials, selective inhibitors produced higher response rates and far fewer patients stopped treatment because of side effects.

How well does selpercatinib work for advanced medullary thyroid cancer?

In a phase III trial of patients who had not received a multikinase inhibitor, 76.4% on selpercatinib were progression-free at 24 months versus 37.2% on cabozantinib or vandetanib. Response rates were 81% in treatment-naïve and 73.5% in previously treated MTC. It does not cure the disease, and resistance eventually develops.

What side effects should I watch for on a selective RET inhibitor?

Common side effects include high blood pressure (22% grade 3 or higher with selpercatinib, 17% with pralsetinib), liver enzyme rises, and low blood counts. Pralsetinib caused lung inflammation in 3% of patients, including one fatal case. Report new cough or shortness of breath promptly, and keep monitoring appointments.

If my first RET inhibitor stops working, are there other options?

Yes. After cabozantinib or vandetanib, selective RET inhibitors still produced responses: 73.5% for selpercatinib and 52.2% for pralsetinib in previously treated MTC. For RET fusion-positive thyroid cancers, response rates were 77.3% to 84.0%. Ask your doctor about clinical trials, because resistance mutations can limit current drugs.

I have advanced RET-mutant medullary thyroid cancer and my doctor recommends cabozantinib or vandetanib first — when should I get a second opinion on that treatment choice?

For advanced, multikinase-inhibitor-naïve RET-mutant MTC, first-line selpercatinib more than doubled 24-month progression-free survival versus cabozantinib or vandetanib (76.4% versus 37.2%), with fewer treatment discontinuations (5% versus 27%) and fewer dose reductions (39% versus 77%). A second opinion can confirm your RET testing was adequate, since DNA-based NGS can miss fusions and a negative liquid biopsy should be confirmed with tissue testing. A second opinion can also review whether a selective RET inhibitor or a clinical trial fits your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: RET kinase inhibitors for the treatment of RET-altered thyroid cancers

Authors: Sarah Hamidi and Mimi I. Hu, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

Publication: Annales d'Endocrinologie, volume 85 (2024), pages 118–126. Published by Elsevier Masson SAS as an open-access article under a CC BY-NC license.

Article type: Review article, published in 2024 to mark the 30th anniversary of the discovery linking germline RET proto-oncogene mutations to the multiple endocrine neoplasia (MEN) type 2 syndromes.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace personalized medical advice from your treating physician.