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. 2024 Nov 1;130(21):3658-3670.
doi: 10.1002/cncr.35465. Epub 2024 Jul 3.

PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation

Dylan J Martini  1 , Katherine B Case  2 , Derrik Gratz  3 , Kathryn Pellegrini  3 , Elizabeth Beagle  3 , Thomas Schneider  4 , Melad Dababneh  4 , Bassel Nazha  5   6 , Jacqueline T Brown  5   6 , Shreyas S Joshi  6   7 , Vikram M Narayan  6   7 , Kenneth Ogan  6   7 , Viraj A Master  6   7 , Bradley C Carthon  5   6 , Omer Kucuk  5   6 , Lara R Harik  4   6 , Mehmet Asim Bilen  5   6
Affiliations

PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation

Dylan J Martini et al. Cancer. .

Abstract

Background: Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin-4 and programmed death ligand-1 (PD-L1) has been reported in BCDD. Importantly, nectin-4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD-L1 expression is associated with responses to immune checkpoint inhibitors (ICIs).

Methods: The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin-4 and PD-L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole-exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs.

Results: The results indicated that nectin-4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD-L1-positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs.

Conclusions: In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

Keywords: RNA sequencing (RNAseq); antibody–drug conjugate; biomarkers, bladder cancer; nectin‐4; programmed death ligand‐1 (PD‐L1); whole‐exome sequencing.

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Conflict of interest statement

Conflict of interest

Mehmet Asim Bilen has acted as a consultant/advisor for and/ or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed as outside of the current study. Bassel Nazha has acted as a paid member of the advisory board of Exelis, as a paid participant in a case discussion for IntrinsiQ Specialty Solutions—AmerisourceBergen, and as a consultant for Cardinal Health. The other authors indicated no financial relationships.

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