B7-H3 (CD276) as a Candidate Therapeutic Target in Medullary Thyroid Cancer

Background: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADC) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. Methods: In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. Results: The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2 and Claudin 18.2 in any evaluable samples. Conclusions: B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.