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. 2023 Dec;21(6):669-678.
doi: 10.1016/j.clgc.2023.05.014. Epub 2023 May 25.

Metastatic Bladder Cancer Expression and Subcellular Localization of Nectin-4 and Trop-2 in Variant Histology: A Rapid Autopsy Study

Fady Ghali  1 , Funda Vakar-Lopez  2 , Martine P Roudier  1 , Jose Garcia  1 , Sonali Arora  3 , Heather H Cheng  4 , Michael T Schweizer  4 , Michael C Haffner  5 , John K Lee  6 , Evan Y Yu  4 , Petros Grivas  4 , Bruce Montgomery  4 , Andrew C Hsieh  7 , Jonathan L Wright  8 , Hung-Ming Lam  9
Affiliations

Metastatic Bladder Cancer Expression and Subcellular Localization of Nectin-4 and Trop-2 in Variant Histology: A Rapid Autopsy Study

Fady Ghali et al. Clin Genitourin Cancer. 2023 Dec.

Abstract

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.

Keywords: Antibody-drug conjugates; Bladder cancer; Metastases; Variant histology.

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Conflict of interest statement

Disclosure Evan Yu: Institutional grants: Daiichi-Sankyo, Taiho, Dendreon, Merck, Seattle Genetics, Blue Earth, Bayer - DAROL and citDNA, Lantheus Consulting with honorarium (in the last 3 years): Jansen, Merck, Advanced Accelerator Applications, Bayer, Exelixis, Clovis, Abbvie, Sanofi-Genzyme Funda Vakar-Lopez: AstraZeneca - Virtual Advisory Board Member on metastatic urothelial cancer Petros Grivas: Institutional grants: Bavarian Nordic; Bristol-Myers Squibb; Clovis Oncology; Debiopharm; Merck KGaA; Gilead; Pfizer; MSD; QED Therapeutics; GlaxoSmithKline; G1 Therapeutics; Mirati Therapeutics Consulting: Aadi Bioscience; AstraZeneca; Asieris Pharmaceuticals, Astellas Pharma, BMS; Boston Gene, CG Oncology, Dyania Health; Exelixis; Lucence Health; Fresenius Kabi, G1 Therapeutics; Gilead; Guardant Health; ImmunityBio; Infinity Pharmaceuticals; Janssen; Merck KGaA; Mirati Therapeutics; MSD; Genentech/Roche; Pfizer; PureTech; Regeneron Pharmaceuticals; QED Therapeutics; Seattle Genetics, Strata Oncology, 4D Pharma PLC, UroGen, Silverback Therapeutics Bruce Montgomery: Institutional grants: AstraZeneca, Janssen Oncology, Clovis Oncology, Astellas Pharma, BeiGene John K. Lee: Institutional grants: Immunomedics Michael Schweizer: Institutional grants: Zenith Epigenetics, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Hoffman-La Roche, Tmunity, SignalOne Bio and Ambrx, Inc. Paid consultant and/or received Honoria: Sanofi, AstraZeneca, PharmaIn and Resverlogix. Jonathan Wright Institutional grants: Merck, Veracyte, Pacific Edge, Janssen, Nucleix. Consultant: Immunity Bio Royalties: UpToDate Other authors declare no potential conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Clinical and specimen information for the bladder cancer rapid autopsy series.
A) Demographics, treatment history, and number of specimens (n=67) analyzed for each patient. B) Tissue source and histology of specimens analyzed.
Fig. 2.
Fig. 2.. RNA expression by specimens in the bladder cancer rapid autopsy series.
A) Absolute RNA expression represented by log2TPM (Transcripts Per Million) value for PVRL4 (Nectin-4) and TACSTD2 (Trop-2). LN denotes lymph node, ‘other’ includes lung, pleura, omentum, mesentery, bowel, vasculature, adrenal gland, pancreas, and abdominal wall. B) Mean-centered RNA expression comparison among the 76 specimens from A). Red denotes higher gene expression; blue denotes lower gene expression. C) Correlation analysis of PVRL4 and TACSTD2 with Pearson correlation coefficient, r = 0.81, p < 0.001.
Fig. 3.
Fig. 3.. Nectin-4 and Trop-2 expression in primary and metastatic BC variants.
A) Representative Nectin-4 and Trop-2 IHC images by histology. Both Nectin-4 and Trop-2 showed prominent membranous and cytoplasmic staining in non-NE variants. In PUC and UCSD, cells with predominantly cytoplasmic staining were noted for Nectin-4 (red arrows). Magnification:400×, scale bar = 50μm. B) H score by specimen (n=67), separated for membranous and cytoplasmic staining. LN denotes lymph node, ‘other’ includes lung, pleura, omentum, mesentery, bowel, vasculature, adrenal gland, pancreas, and abdominal wall. C) Box-and-whisker plot of primary and metastatic H scores, separated by membranous and cytoplasmic subcellular localization (n=67 each). The P value from Mann-Whitney U test was shown.
Fig. 4.
Fig. 4.. Protein expression level and box-and-whisker plot for each histology and specimen site for A) Nectin-4 and B) Trop-2.
The P value from Mann-Whitney U test is shown in the box-and-whisker plot.
See this image and copyright information in PMC

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