The Journal of clinical endocrinology and metabolism · 2025
Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma.
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Xu Bin, Baine Marina K, Jungbluth Achim, Alabkaa Anas, Serrette Rene, Roy Dibisha, Rudin Charles M, Ho Alan L, Sherman Eric, Dogan Snjezana, Ganly Ian, Rekhtman Natasha, Ghossein Ronald
Аннотация
CONTEXT: Seizure-related 6 homolog (SEZ6) is a cDNA that is strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody-drug conjugate targeting SEZ6 has been developed and is currently in a clinical trial for the treatment of SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC).
OBJECTIVE: We herein present the first evidence that SEZ6 is highly expressed in MTC.
METHODS: SEZ6 immuno-expression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile.
RESULTS: SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using 2 different SEZ6 antibody clones, SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immuno-expression determined using H score was associated with male sex, advanced stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations was 83%.
CONCLUSION: SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targeted antibody-drug conjugate therapy a promising targeted therapy for MTCs.
OBJECTIVE: We herein present the first evidence that SEZ6 is highly expressed in MTC.
METHODS: SEZ6 immuno-expression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile.
RESULTS: SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using 2 different SEZ6 antibody clones, SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immuno-expression determined using H score was associated with male sex, advanced stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations was 83%.
CONCLUSION: SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targeted antibody-drug conjugate therapy a promising targeted therapy for MTCs.