Comprehensive analysis of antibody-drug conjugate (ADC) targets in adenoid cystic carcinoma: examining antigen expression in relation to clinicopathological features, prognosis, and initial therapeutic outcomes

Effective systemic therapy for refractory or recurrent/metastatic adenoid cystic carcinoma (ACC) remains an unmet clinical need. Although antibody-drug conjugates (ADCs) have revolutionized treatment for other solid tumors, their application in ACC is limited by an inadequate understanding of targetable antigen expression. We performed immunohistochemical analysis of five ADC targets (EGFR, TROP2, B7-H4, Nectin-4, and AXL) across 265 ACC cases (193 non-solid subtype and 72 solid subtype) and examined their expression in relation to clinicopathological features, histological subtypes, and prognosis. Additionally, we conducted preliminary biomarker-guided ADC therapy in two selected patients. EGFR and TROP2 were frequently expressed at moderate-to-high levels (81% of cases for EGFR and 77% for TROP2), mainly in non-solid ACC, with high expression rates of 72% and 55%, respectively. Conversely, B7-H4 and Nectin-4 showed moderate-to-high expression in 59% and 55% of the overall cohort, but were notably enriched in the aggressive solid subtype, with high expression observed in 66% and 75% of cases, respectively. AXL expression was either negative or low. High B7-H4 and Nectin-4 expression levels were independently associated with reduced overall survival (p < 0.05), whereas EGFR and TROP2 expression showed no significant prognostic value. Importantly, early clinical studies demonstrated that the EGFR-targeted ADC MRG003 and the TROP2-targeted ADC Sac-TMT showed notable efficacy in patients with refractory ACC and high expression of these targets. This pioneering study introduces a biomarker-based stratification system, categorizing ACC patients by histological subtype and target expression profiles, EGFR/TROP2 for non-solid ACC and B7-H4/Nectin-4 for solid ACC, to inform ADC therapy decisions.