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Published on: September 13, 2018
Metastatic Bladder Cancer Expression and Subcellular Localization of Nectin-4 and Trop-2 in Variant Histology: A
Fady Ghali1, Funda Vakar-Lopez2, Martine P Roudier1
1Department of Urology, University of Washington School of Medicine, Seattle, WA.
Background:
Nectin-4 and Trop-2 are transmembrane targets of FDA-approved antibody-drug conjugates (ADC) Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG), respectively, for the treatment of metastatic urothelial carcinoma (mUC). The expression and role of Nectin-4 and Trop-2 in mUC variant histology is poorly described.
Materials And Methods:
We evaluate membranous and cytoplasmic protein expression, and mRNA levels of Nectin-4 and Trop-2 within matched primary and metastatic mUC samples to determine heterogeneity of ADC targets in mUC variants.
Results:
Patients with mUC were consented for rapid autopsy immediately after death. Tissues from matched primary and metastatic lesions were collected. A total of 67 specimens from 20 patients were analyzed: 27 were UC, 17 plasmacytoid (PUC), 18 UC with squamous differentiation (UCSD), and 5 neuroendocrine (NE); 10 from primary and 57 from metastatic sites. All histology except NE expressed moderate-high levels of Nectin-4 and Trop-2 by both immunohistochemistry and RNAseq. Nectin-4 demonstrated prominent cytoplasmic staining in metastatic PUC and UCSD. Trop-2 demonstrated strong cytoplasmic and membrane staining in primary and metastatic tumors. Interestingly, Nectin-4 and Trop-2 expression are positively correlated at both mRNA and protein levels.
Conclusion:
UC and non-NE variants express notable level of Nectin-4 and Trop-2 in both primary and metastatic lesions. Membrane staining of Nectin-4 and Trop-2 is present but cytoplasmic staining is a more common event in both mUC and mUC variant histology. These findings support evaluation of EV and SG in heavily treated variant histology BC and urge attention on the clinical relevance of cytoplasmic localization of ADC targets.
Insights
Nectin-4 and Trop-2 are targets for antibody-drug conjugates (ADCs) in metastatic urothelial carcinoma (mUC). Both targets are expressed in mUC variants, with cytoplasmic localization being common, supporting ADC use in diverse mUC histologies.
Area of Science:
- Oncology
- Molecular Biology
- Translational Research
Background:
- Nectin-4 and Trop-2 are transmembrane targets for FDA-approved antibody-drug conjugates (ADCs) Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG).
- These ADCs are used to treat metastatic urothelial carcinoma (mUC).
- The expression and role of Nectin-4 and Trop-2 in mUC variant histology are not well understood.
Purpose of the Study:
- To evaluate Nectin-4 and Trop-2 expression in matched primary and metastatic mUC samples.
- To determine the heterogeneity of ADC targets across different mUC variant histologies.
- To assess both membranous and cytoplasmic protein expression, alongside mRNA levels.
Main Methods:
- Rapid autopsy tissue collection from 20 patients with mUC.
- Analysis of 67 specimens (primary and metastatic lesions) including urothelial carcinoma (UC), plasmacytoid (PUC), UC with squamous differentiation (UCSD), and neuroendocrine (NE) variants.
- Immunohistochemistry and RNA sequencing to assess Nectin-4 and Trop-2 expression.
Main Results:
- Nectin-4 and Trop-2 were expressed at moderate-high levels in all mUC variants except NE.
- Cytoplasmic staining for Nectin-4 was prominent in metastatic PUC and UCSD.
- Nectin-4 and Trop-2 expression positively correlated at both mRNA and protein levels.
Conclusions:
- UC and non-NE variants exhibit significant Nectin-4 and Trop-2 expression in primary and metastatic sites.
- Cytoplasmic localization of these targets is more common than membrane staining across mUC and its variants.
- Findings support the evaluation of EV and SG in heavily treated variant histology bladder cancer, highlighting the clinical relevance of cytoplasmic target localization.
