Trop2 Expression in Vulvar Squamous Cell Carcinomas: Implications for Targeted Therapy

Overview of Vulvar Squamous Cell Carcinomas and Their Subtypes

Vulvar cancer accounts for approximately 0.2% of all cancer cases globally, with the majority being squamous cell carcinomas (SCC) (Condic et al., 2023). The classification of VSCC has evolved, revealing distinct molecular subtypes based on human papillomavirus (HPV) status and p53 mutation patterns. The two primary subtypes are:

1. HPV-associated VSCC (p16+ve/p53wt): Characterized by the overexpression of p16 and wild-type p53, this subtype typically has a better prognosis due to its association with a more favorable response to treatments.

2. HPV-independent VSCC (p16−ve/p53abn): This subtype is marked by aberrant p53 expression and is associated with poorer outcomes. It often arises in older women and is linked to chronic inflammatory conditions, such as lichen sclerosus (Kortekaas et al., 2020).

The growing understanding of these subtypes has significant implications for treatment strategies, as the choice of therapy can vary markedly based on the molecular characteristics of the tumor.

Significance of Trop2 as a Marker in Cancer Therapy

Trop2 is a transmembrane glycoprotein that plays a critical role in cell proliferation and survival. Overexpression of Trop2 has been observed in various cancers, including breast, lung, and colorectal cancers (Liu et al., 2013). Its expression correlates with aggressive disease characteristics, making it an attractive target for antibody-drug conjugates (ADCs). For instance, Sacituzumab Govitecan, an FDA-approved Trop2-targeting ADC, has shown efficacy against triple-negative breast cancer (Bardia et al., 2021).

The potential for Trop2-targeted therapies in VSCC is underscored by findings indicating high expression levels in the majority of VSCC cases, regardless of molecular subtype (Höhn et al., 2025). This suggests that Trop2 could serve as a universal target for both HPV-positive and HPV-negative VSCC, paving the way for more effective treatments.

Immunohistochemical Analysis of Trop2 in VSCC Biopsies

Recent studies have implemented immunohistochemical techniques to evaluate Trop2 expression levels in diagnostic biopsies from VSCC patients. The expression is scored using an immunoreactive score (IRS) that considers both the intensity of staining and the percentage of positive cells. In a cohort of 57 VSCC cases, moderate to strong expression of Trop2 was observed in over 88% of tumors, highlighting its potential role as a therapeutic target (Höhn et al., 2025).

This table illustrates the prevalence of Trop2 expression across different molecular subtypes of VSCC, demonstrating the potential for Trop2 ADCs to target both HPV-positive and HPV-negative tumors effectively.

Correlation Between Trop2 Expression and Molecular Subtypes

The correlation between Trop2 expression and the molecular subtypes of VSCC has significant clinical implications. The study by Höhn et al. (2025) indicated that while Trop2 expression was uniformly high across all subtypes, the highest levels were observed in HPV-associated tumors. This suggests that Trop2 could serve not only as a target for ADCs but also as a biomarker for predicting treatment response and survival outcomes.

In clinical practice, the assessment of Trop2 expression can aid oncologists in stratifying patients for targeted therapies. Given the aggressive nature of HPV-independent VSCC, identifying high Trop2 expressions may indicate a need for immediate intervention with Trop2-targeted therapies.

Potential of Trop2-Directed Antibody-Drug Conjugates in Treatment

The therapeutic landscape for VSCC could be transformed by the introduction of Trop2-directed ADCs, leveraging their high expression in tumors. These ADCs combine the targeting capability of monoclonal antibodies with potent cytotoxic agents, minimizing off-target effects and maximizing therapeutic efficacy. Current trials are exploring the use of Trop2 ADCs in various cancers, and their application in VSCC is warranted given the promising expression data.

The ongoing research into Trop2-targeting therapies could potentially lead to new treatment protocols for VSCC, particularly for patients with advanced disease that has limited treatment options. Early results from studies on ADCs like Sacituzumab Govitecan indicate that they can significantly reduce tumor burden and improve overall survival rates (Bardia et al., 2021).

FAQ Section

What is Trop2 and why is it important in cancer therapy?
Trop2 is a transmembrane glycoprotein that is overexpressed in various cancers, including vulvar squamous cell carcinomIts expression correlates with aggressive disease characteristics, making it a promising target for antibody-drug conjugates (ADCs) that can deliver cytotoxic agents directly to cancer cells.

How does Trop2 expression vary among different molecular subtypes of VSCC?
Trop2 expression is generally high across all molecular subtypes of VSCC, including HPV-positive and HPV-negative tumors. However, the highest expression levels are typically seen in HPV-associated tumors, which may correlate with better treatment responses.

What are antibody-drug conjugates (ADCs) and how do they work?
ADCs are a type of targeted cancer therapy that combines an antibody, which specifically binds to cancer cells, with a cytotoxic drug. This allows for the selective delivery of the drug to cancer cells, minimizing damage to normal cells and enhancing treatment efficacy.

Are there any ongoing clinical trials for Trop2-targeting therapies in VSCC?
Yes, there are ongoing clinical trials assessing the efficacy of Trop2-targeting therapies, such as Sacituzumab Govitecan, in various cancers, including vulvar squamous cell carcinomResults from these trials may provide new treatment options for patients.

Why is it essential to identify Trop2 expression in VSCC?
Identifying Trop2 expression in VSCC can guide treatment decisions for targeted therapies and may improve patient outcomes by allowing for personalized treatment plans based on the tumor’s molecular characteristics.

References

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2. Condic, M., Egger, E. K., Klümper, N., Kristiansen, G., Mustea, A., Thiesler, T., et al. (2023). TROP-2 is widely expressed in vulvar squamous cell carcinoma and represents a potential new therapeutic target. Journal of Cancer Research and Clinical Oncology, 149(11), 8235-8241. Retrieved from https://pubmed.ncbi.nlm.nih.gov/37067548/

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