Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)
The MEN syndromes are inherited faults in a single gene that cause tumours in several hormone glands over a lifetime. Because the gene can be found in childhood, at-risk relatives can be tested, watched and in MEN2 have the thyroid removed before cancer develops; and for MEN2 thyroid cancer that does spread there is now a precise pill, selpercatinib, that blocks the faulty RET protein.
Overview
MEN1 is caused by germline loss-of-function mutations in MEN1, encoding the tumour suppressor menin, and produces parathyroid hyperplasia (nearly universal), duodenopancreatic neuroendocrine tumours (gastrinoma, insulinoma, non-functioning PanNETs, the main cause of death), anterior pituitary tumours, and adrenal, thymic and bronchial neuroendocrine tumours. MEN2 is caused by germline activating mutations in the RET receptor tyrosine kinase: MEN2A (codon 634 most often) causes medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid disease; MEN2B (M918T) causes early aggressive MTC, pheochromocytoma, mucosal neuromas and a marfanoid habitus. MEN4 (CDKN1B) is a rare MEN1 phenocopy. These syndromes are on the NCI list because their management is oncological: surveillance, prophylactic surgery and, when tumours spread, targeted therapy.
Management is genotype-driven. In MEN2, the American Thyroid Association (2015) assigns RET codons to risk levels that set the age of prophylactic thyroidectomy (within the first year for M918T, before age 5 for codon 634, later with calcitonin monitoring for moderate-risk codons), an intervention that prevents MTC in carriers identified early. Pheochromocytoma must be excluded before any surgery. Advanced RET-mutant MTC is treated with selpercatinib, which outperformed cabozantinib or vandetanib in the randomised LIBRETTO-531 trial (NEJM 2023), with pralsetinib as an alternative. In MEN1, surveillance (calcium and PTH, gastrin and fasting gut hormones, pituitary hormones, pancreatic MRI or endoscopic ultrasound) begins in childhood; parathyroidectomy, proton pump inhibitors for gastrinoma, and surgery for PanNETs above about 2 cm or functioning; advanced PanNETs are treated as sporadic NETs with somatostatin analogues, everolimus, sunitinib and 177Lu-DOTATATE.
Open problems are the timing of pancreatic surgery in MEN1, the lack of menin-directed therapy for MEN1 tumours (menin inhibitors developed for leukaemia work by a different mechanism), and equitable access to genetic testing and lifelong surveillance.
State of the art today
- MEN2 is the clearest example of genotype-directed prevention in oncology: a RET codon result sets the age of an operation that prevents a lethal cancer.
- Selpercatinib converted RET-mutant MTC from multikinase-inhibitor territory into precision oncology, with better responses and fewer toxicities in a randomised comparison.
- MEN1 surveillance protocols detect pancreatic NETs early, and 68Ga-DOTATATE PET and endoscopic ultrasound have replaced CT for pancreatic screening in many centres.
- Cascade genetic testing of relatives, often in childhood, is standard and effective.
Where it starts and where it drains
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
- Oral cavity and tongue
- Oropharynx: tonsil, base of tongue (HPV)
- Nasopharynx (EBV)
- Larynx and hypopharynx
- Parotid and other salivary glands
- ThyroidMEN1 (menin; parathyroid, pancreatic NET, pituitary) · MEN2A (RET; medullary thyroid carcinoma, pheochromocytoma, parathyroid) · MEN2B (RET M918T; early MTC, pheochromocytoma, mucosal neuromas) · Familial medullary thyroid carcinoma (MEN2A variant)
- level I (submandibular)
- level II (upper jugular)
- level III-IV (jugular)
- level V (posterior)
- level VI (central, thyroid)
- retropharyngeal (nasopharynx)
Same organ: Head and neck squamous cell carcinoma, Nasopharyngeal carcinoma, Salivary gland cancers, Thyroid cancer, Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), NUT carcinoma (midline carcinoma with NUTM1 rearrangement), Parathyroid carcinoma
MEN1 affects about 2 to 3 per 100,000 people and MEN2 about 1 in 30,000; both are inherited in an autosomal dominant pattern with near-complete penetrance.
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Prophylactic total thyroidectomy timed by ATA risk level (highest risk within the first year, high risk before age 5, moderate risk guided by calcitonin); annual screening for pheochromocytoma and hyperparathyroidism.
Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives.
Surveillance from childhood; subtotal or total parathyroidectomy with autotransplantation for hyperparathyroidism; proton pump inhibitors for gastrinoma; resection of functioning or larger PanNETs; sporadic NET pathways (somatostatin analogues, everolimus, sunitinib, PRRT) for advanced disease.
Subtypes & biomarkers
top- MEN1 (menin; parathyroid, pancreatic NET, pituitary)
- MEN2A (RET; medullary thyroid carcinoma, pheochromocytoma, parathyroid)
- MEN2B (RET M918T; early MTC, pheochromocytoma, mucosal neuromas)
- Familial medullary thyroid carcinoma (MEN2A variant)
- MEN4 (CDKN1B)
- Germline MEN1, RET or CDKN1B mutation (diagnostic; codon defines MEN2 risk level)
- Calcitonin and CEA (MTC surveillance)
- Calcium and PTH, gastrin, fasting glucose and insulin, prolactin and IGF-1 (MEN1 surveillance)
- Plasma metanephrines before any surgery (pheochromocytoma exclusion)
- Pancreatic imaging (MRI, endoscopic ultrasound, 68Ga-DOTATATE PET)
Target prevalence in this cancer
- 1954Wermer describes familial adenomatosis of endocrine glands (MEN1)
- 1961Sipple describes the association of pheochromocytoma and thyroid carcinoma (MEN2)
- 1993RET mutations cause MEN2A
Mulligan and colleagues, Nature; Donis-Keller and colleagues.
- 1997MEN1 gene cloned
Chandrasekharappa and colleagues, Science; menin identified.
- 2015ATA guideline: codon-based timing of prophylactic thyroidectomy
- 2020Selpercatinib and pralsetinib approved for RET-mutant MTC
- 2023LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC
Hadoux and colleagues, NEJM.
Open problems, and what is being done about each
MEN1 has no menin-restoring or pathway-directed therapy; PanNET progression remains the main cause of death, addressed by earlier detection and NET therapies.
Timing and extent of pancreatic surgery in MEN1: prospective registries are comparing strategies.
Resistance to selpercatinib (RET solvent-front mutations): next-generation RET inhibitors are in trials.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- CabozantinibApproved
- Small-molecule kinase inhibitorsStandard of care
- AmivantamabApproved
- CamizestrantApproved
- Comprehensive genomic profilingStandard of care
- Liquid biopsy (ctDNA)Standard of care
In trials- ADC payload neutralisersPhase 1
- BGB-16673Phase 3
- Bispecific ADCPhase 3
- BRUIN CLL-321Positive
- CaDAnCe-304Recruiting
- CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)Active
Ideas and roadmaps- A clone report from blood at every treatment cycle
- A fast route to the matched drug when it is licensed for another cancer
- A multi-cancer platform trial of adaptive (dose-holiday) therapy
- A national rapid research autopsy network for end-stage cancer
- A standard evolvability score for every tumour
- A standing platform trial that assigns treatment by how the tumour escaped
Background: ADC sequencing, Antigen escape (antigen loss, lineage switch), BCG-unresponsive, Castration-resistant prostate cancer (CRPC), Circulating tumour DNA (ctDNA). Also on OnCo: Resistance atlas: how tumours escape and what closes the route · Lines of therapy.
Lifelong surveillance costs and psychological burden in carriers identified as children.
and how the field plans to fix it →What is being done about thisCost and accessAvailable now- HPV & HBV vaccinationStandard of care
- ImatinibApproved
- Trastuzumab biosimilarsApproved
In trials- Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)Positive
- IARC India HPV vaccine dose study (one, two or three doses)Positive
- IMAGINE (varnimcabtagene autoleucel, Immuneel)Positive
- Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)Positive
- Low-dose olanzapine for cancer anorexia (Tata Memorial)Positive
- METRO PLUS (Tata Memorial Centre, Varanasi)Positive
Ideas and roadmaps- 90-day reliance approval for cancer drugs cleared by two stringent regulators
- A cheap old tablet to restore appetite
- A combination pricing rule so two-drug regimens are not priced as two monopolies
- A coordinated reserve and shared schedule for the world's medical isotope reactors
- A dedicated global financing window for cancer, modelled on the Global Fund
- A delinked market-entry reward paid by payers when a repurposed generic wins approval
Background: Accelerated approval, Biosimilar, Real-world evidence. Also on OnCo: Financial help and assistance navigator · Coverage by country · HTA decisions.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Landmark trials in OnCo
Expert centres
topCentres linked to this cancer in OnCo
- via Thyroid cancer, Neuroendocrine tumours
- via Thyroid cancer
- via Thyroid cancer
- via Neuroendocrine tumours
- via Neuroendocrine tumours
- via Neuroendocrine tumours
- Peking Union Medical College HospitalBeijing, CNvia Thyroid cancer, Germline (hereditary) testing, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- Erasmus MC Cancer InstituteRotterdam, NLvia Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Thyroid cancer, Germline (hereditary) testing
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- via Lutetium-177 dotatate, Neuroendocrine tumours
- A.C. Camargo Cancer CenterSão Paulo, BRvia Germline (hereditary) testing
- Alliance for Clinical Trials in OncologyChicago, IL, USvia Neuroendocrine tumours
- ASST Spedali Civili di BresciaBrescia, ITvia Thyroid cancer
- via Neuroendocrine tumours
- Cancer Research UKLondon, GBvia Thyroid cancer
- Catalan Institute of Oncology (ICO)L'Hospitalet de Llobregat, ESvia Germline (hereditary) testing
- Children's Hospital of PhiladelphiaPhiladelphia, PA, USvia Germline (hereditary) testing
- ECOG-ACRIN Cancer Research GroupPhiladelphia, PA, USvia Neuroendocrine tumours
- Edinburgh Cancer Centre / CRUK Scotland CentreEdinburgh, GBvia Germline (hereditary) testing
- European Association of Nuclear MedicineVienna, ATvia Lutetium-177 dotatate
- First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, CNvia Thyroid cancer
- via Germline (hereditary) testing
- via Germline (hereditary) testing
- Groote Schuur Hospital / University of Cape TownCape Town, ZAvia Germline (hereditary) testing
- Hadassah Medical CenterJerusalem, ILvia Germline (hereditary) testing
- via Germline (hereditary) testing
- Hospital de Clínicas de Porto AlegrePorto Alegre, BRvia Germline (hereditary) testing
- Hospital Universitari i Politècnic La FeValencia, ESvia Germline (hereditary) testing
- via Germline (hereditary) testing
- via Germline (hereditary) testing
- via Germline (hereditary) testing
- IRCCS Ospedale San RaffaeleMilan, ITvia Neuroendocrine tumours
- King Hussein Cancer CenterAmman, JOvia Germline (hereditary) testing
- Korle Bu Teaching HospitalAccra, GHvia Germline (hereditary) testing
- Kyushu University HospitalFukuoka, JPvia RET
- Lagos University Teaching HospitalLagos, NGvia Germline (hereditary) testing
- MovemberMelbourne, AUvia Germline (hereditary) testing
- National Cancer Center Hospital EastKashiwa, Chiba, JPvia RET
- National Cancer Center KoreaGoyang, KRvia Thyroid cancer
- QIMR Berghofer Medical Research InstituteBrisbane, AUvia Germline (hereditary) testing
- Ramathibodi Hospital, Mahidol UniversityBangkok, THvia Germline (hereditary) testing
- via Neuroendocrine tumours
- Shaare Zedek Medical CenterJerusalem, ILvia Germline (hereditary) testing
- Shanghai Chest HospitalShanghai, CNvia RET
- Shizuoka Cancer CenterNagaizumi, Shizuoka, JPvia Germline (hereditary) testing
- via Germline (hereditary) testing
- Society of Nuclear Medicine and Molecular ImagingReston, VA, USvia Lutetium-177 dotatate
- Tawam HospitalAl Ain, AEvia Thyroid cancer
- The Hospital for Sick Children (SickKids)Toronto, ON, CAvia Germline (hereditary) testing
- Tohoku University HospitalSendai, JPvia Germline (hereditary) testing
- via Neuroendocrine tumours
- University Hospital Düsseldorf / CIO DüsseldorfDüsseldorf, DEvia Neuroendocrine tumours
- University of Malaya Medical CentreKuala Lumpur, MYvia Germline (hereditary) testing
Questions to ask
topQuestions to ask your oncologist about Multiple endocrine neoplasia syndromes
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Germline MEN1, RET or CDKN1B mutation, Calcitonin and CEA, Calcium and PTH, gastrin, fasting glucose and insulin, prolactin and IGF-1, Plasma metanephrines before any surgery, Pancreatic imaging), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include MEN1, MEN2A, MEN2B.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
MEN2 carriers (RET-positive)
- For my situation (men2 carriers (ret-positive)), which of the standard options do you recommend and why?Why: Guideline options include: Prophylactic total thyroidectomy timed by ATA risk level (highest risk within the first year, high risk before age 5, moderate risk guided by calcitonin); annual screening for pheochromocytoma and hyperparathyroidism.
Advanced RET-mutant medullary thyroid carcinoma
- For my situation (advanced ret-mutant medullary thyroid carcinoma), which of the standard options do you recommend and why?Why: Guideline options include: Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives.
- Am I a candidate for Selpercatinib, Pralsetinib, Cabozantinib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of LIBRETTO-531 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
MEN1 carriers
- For my situation (men1 carriers), which of the standard options do you recommend and why?Why: Guideline options include: Surveillance from childhood; subtotal or total parathyroidectomy with autotransplantation for hyperparathyroidism; proton pump inhibitors for gastrinoma; resection of functioning or larger PanNETs; sporadic NET pathways (somatostatin analogues, everolimus, sunitinib, PRRT) for advanced disease.
- Am I a candidate for Somatostatin analogues (octreotide, lanreotide), Everolimus, Sunitinib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Selpercatinib, LIBRETTO-531, Lutetium-177 dotatate, Everolimus?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “MEN1 has no menin-restoring or pathway-directed therapy; PanNET progression remains the main cause of death, addressed by earlier detection and NET therapies”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Timing and extent of pancreatic surgery in MEN1: prospective registries are comparing strategies”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
6targets
9drugs
8companies
6pathways
3terms
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1bottlenecks
2Latest papers
topQuery for this cancer: (TITLE:"Multiple endocrine neoplasia syndromes" OR ABSTRACT:"Multiple endocrine neoplasia syndromes" OR TITLE:"MEN1, MEN2, MEN4" OR ABSTRACT:"MEN1, MEN2, MEN4" OR TITLE:"MEN1" OR ABSTRACT:"MEN1" OR TITLE:"MEN2A" OR ABSTRACT:"MEN2A" OR TITLE:"MEN2B" OR ABSTRACT:"MEN2B" OR TITLE:"MEN4" OR ABSTRACT:"MEN4") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), not a curated reading list.
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