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Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) infection. Despite these advancements in our understanding, utilization of targeted therapies remains limited and underexplored. In this study, we evaluated the transcript and protein expression of Nectin-4 (PVRL4) in PSCC tumors and evaluated whether this is related to tumor features or clinical outcomes. Using two separate PSCC cohorts, we demonstrate that the majority of tumors have active transcription of Nectin-4. We then validated our findings using immunohistochemistry in a tissue microarray representing 57 patients with PSCC. We identified that Nectin-4 was expressed at higher levels in patients with high-risk HPV infection. No significant differences were identified in tumor characteristics or various clinical endpoints when comparing tumors with high and low Nectin-4 expression. This study demonstrates that Nectin-4 is expressed in PSCC and may represent a novel therapeutic target., Patient Summary: In this study, we evaluated the expression of Nectin-4, a cell surface protein, in tumors from patients with nonmetastatic penile squamous cell carcinoma (PSCC). To our knowledge, this is the first study to describe elevated expression of Nectin-4 in PSCC, which may suggest its utility as a therapeutic target., (© 2023 The Author(s).)

Radiation therapy (RT) has not been prominent in the treatment of penile cancer because of poorly reproducible results when used in the adjuvant setting. A genomic signature has recently been described that assays radiosensitivity of tumors and informs radiotherapy doses in these cases. Clinical validation in more than 1600 patients demonstrated associations with both overall survival and time to first recurrence. In addition, the signature predicted and quantified the therapeutic benefit of RT for each individual patient. Since penile cancer patients were not part of this analysis, we applied the model to patients with primary and nodal penile cancer tissue and clinical outcomes. Patient summary : Radiotherapy has not been widely used for treatment of penile cancer. New genetic data suggest that radiation doses commonly used to treat penile cancer are too low. This would explain prior poor results using radiation in this disease., (© 2021 The Author(s).)