Assessment of Nectin4-expression in vulvar squamous cell carcinomas (VSCC): correlation with HPV-associated and HPV-independent molecular subtypes.

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/p53  molecular subtype: 12/14 (85.7 %) when compared to HPV-independent VSCC (22/35 (62.9 %) in p16/p53 and 0 % in four p16/p53 ) 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/p53 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.