Skip to main content
ENDO 2026 Main banner

Tumor Biology

SAT-296 - MEN2A Secondary to the RET P.K666N Pathogenic Variant: Phenotype Expression in an Increasingly Diagnosed Disease

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Mimi I. Hu, MD: Eli Lilly & Company: Advisory Board (), Clinical Trial Investigator (), Speakers' Bureau ()


Background:
The RET p.K666N (c.1998G>T) germline pathogenic variant (PV), increasingly identified incidentally, is a rare cause of MEN2A with low penetrance of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT). Very little is known about its phenotypic expression and management of patients (pts) with this PV.

Methods:
Using institutional databases at a tertiary cancer center, we conducted a retrospective cohort study of pts with a RET p.K666N germline PV. We assessed the prevalence and age of onset of MTC, PHEO, and PHPT.

Results:
We identified 39 pts (69% F) diagnosed with MEN2A at a median age at diagnosis of 45 yrs (range 0-69): 17 (44%) incidentally on genetic testing done for other indications, 13 (33%) due to cascade testing, and 9 (23%) after MTC diagnosis. 12/39 (31%) pts had MTC, 2 (5%) had PHEO (1 isolated; 1 with MTC [homozygous genotype]), and none had PHPT.
Among 12 patients diagnosed with MTC (median age 45.5 yrs; range 23-59), 7 (58%) presented due to MTC (median age 45.8 yrs; range 23-59), 2 (17%) were incidentally found after thyroidectomy for other reasons (both 50 yrs), 2 (17%) were identified after risk reducing thyroidectomy (RRT) (ages 44 and 45 yrs), and 1 (8%) was unknown (age 23 yrs). Preoperative CTN level was elevated in both pts who underwent RRT (15.9 and 25.1 pg/mL) and in the 5 evaluable pts with clinical MTC (median 48 pg/mL; range 7-1441). Staging was available in 8 pts, with 2 pts each grouped as stage 1, 3, 4A and 4C. Median follow-up time from MTC diagnosis was 9.4 yrs (range 1-43) and the median age at follow-up was 52.5 yrs (range 33-66). At last follow-up, 3 pts (25%) had no evidence of disease, 6 (50%) had biochemical disease, and 3 (25%) had structural disease, 2 of whom were stage 4C at initial diagnosis. None required systemic therapy or died.
Among 27 carriers without MTC, CTN was elevated in 2/25 evaluable pts: a toddler with physiologic elevation (normal ultrasound) and a 57-yr old woman with subcentimeter thyroid nodules and a stable clinical course over 9.5 yrs. In 2 pts with incidental MEN2A, CTN levels were not available, but both had no imaging evidence of thyroid nodules. RRT was performed in 2 pts, one with C-cell hyperplasia (CTN undetectable) and the other with benign multinodular goiter (CTN N/A). After a median follow up of 1.2 years (range 0-10 yrs) 0/25 pts not undergoing thyroidectomy had been diagnosed with MTC.
Both patients with PHEO (ages 51 and 59 yrs) underwent adrenalectomy, one of whom had additional germline testing with no other PVs in PHEO susceptibility genes found.

Conclusion:
The RET p.K666N germline PV is a rare cause of MEN2A but is increasingly being identified incidentally. Our study highlights the variability in phenotype expression and low penetrance among PV carriers, underscoring the importance of individualized surveillance and a more conservative approach to management as we learn more about this PV.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*