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Assessment of Nectin4-expression in vulvar squamous cell carcinomas (VSCC): correlation with HPV-associated and
Anne Kathrin Höhn1, Grit Gesine Ruth Hiller1, Benjamin Wolf2
1Division of Gynecologic, Breast and Perinatal Pathology, Institute of Pathology, University Hospital Leipzig, Germany.
Background:
The development of antibody-drug conjugates (ADC) for cancer treatment has achieved promising results in different solid tumors and targets. Enfortumab-Vedotin (EV), a humanised anti-Nectin4-IgG1 monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE), is an FDA-approved Nectin4-directed ADC for the treatment of locally advanced or metastatic pre-treated urothelial cancer. Targeted therapy with EV requires the expression of Nectin4 within the tumor cells. The present study evaluates Nectin4 expression in vulvar squamous cell carcinomas (VSCC) and its correlation to different VSCC molecular subtypes.
Methods:
Immunohistochemical Nectin4-expression was evaluated semiquantitatively on diagnostic biopsies of VSCC using an immunoreactive score (IRS). There was a correlation between IRS and different molecular subtypes of VSCC.
Results:
All 55 cases showed at least weak Nectin4 expression within the tumor cells with a median IRS of 6.0 (range 2-6) indicating high expression levels in most tumors. Moderate/high expression (IRS ≥4) was more frequent in HPV-associated tumors (p16+ve/p53 wt molecular subtype: 12/14 (85.7 %) when compared to HPV-independent VSCC (22/35 (62.9 %) in p16-ve/p53abn and 0 % in four p16-ve/p53 wt) VSCC, a difference that is not statistically significant.
Conclusion:
Most VSCC show high expression of Nectin4, including the HPV-independent VSCC containing a TP53-mutation (p16-ve/p53abn molecular subtype), that are associated with the worst prognosis. Therefore, Nectin4-directed ADC such as Enfortumab-Vedotin (EV) may present a potential treatment option in VSCC. Nectin4-expression can easily be assessed by immunohistochemistry on diagnostic biopsies. Clinical trials exploring Nectin4-directed ADCs such as EV are necessary.
Insights
Most vulvar squamous cell carcinomas (VSCC) express Nectin4, a target for antibody-drug conjugates (ADCs). This suggests Enfortumab-Vedotin (EV) could be a potential treatment for VSCC, warranting further clinical trials.
Area of Science:
- Oncology
- Translational Research
- Molecular Pathology
Background:
- Antibody-drug conjugates (ADCs) show promise in treating solid tumors.
- Enfortumab-Vedotin (EV) is an approved Nectin4-targeted ADC for urothelial cancer.
- Nectin4 expression is crucial for ADC efficacy.
Purpose of the Study:
- To assess Nectin4 expression in vulvar squamous cell carcinomas (VSCC).
- To correlate Nectin4 expression with VSCC molecular subtypes.
- To evaluate the potential of Nectin4-targeted ADCs in VSCC treatment.
Main Methods:
- Immunohistochemistry (IHC) was used to evaluate Nectin4 expression.
- Nectin4 expression was semiquantitatively scored (IRS) on 55 VSCC biopsies.
- Correlation analysis between Nectin4 IRS and VSCC molecular subtypes (HPV-associated, HPV-independent).
Main Results:
- All VSCC cases exhibited Nectin4 expression (median IRS 6.0).
- High Nectin4 expression (IRS >4) was observed in 85.7% of HPV-associated tumors and 62.9% of HPV-independent tumors.
- Nectin4 expression was consistently high across different molecular subtypes, including prognostically unfavorable ones.
Conclusions:
- The majority of VSCCs demonstrate high Nectin4 expression.
- Nectin4-targeted ADCs, like Enfortumab-Vedotin (EV), represent a potential therapeutic strategy for VSCC.
- Nectin4 assessment via IHC is feasible, supporting the need for clinical trials of EV in VSCC.
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