Expression patterns of TROP2 and Nectin-4 in oropharyngeal squamous cell carcinoma in relation to HPV status: potential biomarkers for targeted therapy

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Background: Patients with inoperable or metastatic oropharyngeal squamous cell carcinoma (OSCC) face limited therapeutic options. Nectin-4, an immunoglobulin-like transmembrane adhesion protein, and Trophoblast Surface Antigen 2 (TROP2), a transmembrane glycoprotein, have recently emerged as targets for antibody–drug conjugates (ADCs). Enfortumab Vedotin , an ADC targeting Nectin-4, has been approved for locally advanced or metastatic urothelial carcinoma, while sacituzumab govitecan , targeting TROP2, was approved for metastatic triple-negative breast cancer. Objectives: This study aimed to demonstrate expression rates of TROP2 and Nectin-4 in a representative cohort of human papillomavirus (HPV)-positive and HPV-negative OSCC and discuss the relevance of those markers as possible targets for ADCs. Design: A retrospective cohort study. Methods: We analyzed tissue samples from 226 OSCC patients treated at the University Hospital of Cologne between 2005 and 2020. The expression of Nectin-4 and TROP2 was assessed using immunohistochemistry, and the H-score method was applied to categorize expression levels into four groups: negative (0–10), low (11–100), moderate (101–200), and high (201–300). Results: TROP2 expression was positive in 96.5% of the samples, with 84.1% showing moderate to high expression (H-Score 101–300). A total of 38.8% of the cases expressed Nectin-4. Notably, patients with HPV-positive OSCC demonstrated significantly higher Nectin-4 expression compared to those with HPV-negative OSCC ( p < 0.001). Conclusion: This study is one of the first to investigate the expression of Nectin-4 and TROP2 in a cohort of both HPV-positive and HPV-negative OSCC patients. Our results indicate that TROP2 is almost universally expressed in OSCC, while Nectin-4 expression is less frequent. TROP2 and Nectin-4 are promising therapeutic targets for OSCC, with Nectin-4 being particularly relevant for HPV-positive patients. Clinical trials are necessary to confirm the clinical relevance and efficacy of ADCs targeting TROP2 and Nectin-4 in OSCC treatment.

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