Detection of SEZ6, a therapeutic target, in medullary thyroid carcinoma.

Purpose: Seizure-related 6 homolog (SEZ6) is a cDNA that 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 clinical trial in treating SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC). We herein presented the first evidence that SEZ6 was highly expressed in MTC.

Methods: SEZ6 immunoexpression 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 two 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 immunoexpression determined using H score was associated with male sex, advance 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 were 83%.

Main Conclusions: 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-targetted antibody-drug conjugate therapy a promising targeted therapy for MTCs.