Screening of potential antibody-drug conjugate (ADC) targets in neuroendocrine carcinoma of the cervix: implications for targeted therapy.

Abstract

Objective: Neuroendocrine carcinoma of the cervix (NECC) is a rare yet aggressive malignancy with a poor prognosis. Although antibody-drug conjugates (ADCs) have shown promise in multiple cancers, the expression profiles of relevant ADC targets in NECC remain unclear. This study aimed to systematically evaluate candidate ADC target expression in NECC and explore associations with clinicopathological features and prognosis.

Methods: This study assessed the immunohistochemical expression of 9 ADC targets (including B7-H3, ROR1, DLL3, EGFR, Bcl-2, Nectin-4, TF, c-MET, and SEZ6) in a cohort. Expression levels were semi-quantitatively evaluated and correlated with clinicopathological variables and survival.

Results: This study enrolled 173 NECC patients (median age 47 years). Recurrence and mortality rates were 44.5% and 25.4%, respectively. Immunohistochemical profiling was performed in 91 cases with available paraffin-embedded tissues. Near-universal expression of B7-H3 (97.8%) was observed, along with frequent expression of ROR1 (73.6%) and DLL3 (72.5%). Regarding clinicopathological correlations, high B7-H3 expression was associated with parametrial invasion (p=0.039), and EGFR positivity was linked to uterosacral ligament invasion (p=0.034). Among all markers analyzed, only EGFR positivity was significantly associated with increased recurrence risk (p=0.048). Multivariable analysis identified vaginal invasion (hazard ratio [HR]=2.15) and advanced International Federation of Gynecology and Obstetrics stage (HR=3.02) as independent predictors of recurrence (p<0.001).

Conclusion: This study identifies B7-H3 as the premier ADC target in NECC, with ROR1 and DLL3 as additional promising targets. EGFR demonstrates dual utility for prognostic stratification and therapeutic intervention. These findings provide molecular evidence to guide the development of precision therapy for this aggressive malignancy.