CK5/6 and GATA3 Defined Phenotypes of Muscle-Invasive Bladder Cancer: Impact in Adjuvant Chemotherapy and Molecular Subtyping of Negative Cases

Florestan J Koll; Alina Schwarz; Jens Köllermann; Severine Banek; Luis Kluth; Clarissa Wittler; Katrin Bankov; Claudia Döring; Nina Becker; Felix K H Chun; Peter J Wild; Henning Reis

doi:10.3389/fmed.2022.875142

CK5/6 and GATA3 Defined Phenotypes of Muscle-Invasive Bladder Cancer: Impact in Adjuvant Chemotherapy and Molecular Subtyping of Negative Cases

Front Med (Lausanne). 2022 Jun 16:9:875142. doi: 10.3389/fmed.2022.875142. eCollection 2022.

Authors

Florestan J Koll^{1

2

3}, Alina Schwarz⁴, Jens Köllermann⁴, Severine Banek¹, Luis Kluth¹, Clarissa Wittler¹, Katrin Bankov⁴, Claudia Döring⁴, Nina Becker^{3

4}, Felix K H Chun¹, Peter J Wild^{2

4

5}, Henning Reis⁴

Affiliations

¹ Department of Urology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
² Frankfurt Cancer Institute (FCI), University Hospital, Goethe University, Frankfurt, Germany.
³ University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University, Frankfurt, Germany.
⁴ Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany.
⁵ Frankfurt Institute for Advanced Studies, Frankfurt, Germany.

Abstract

Introduction and objective: Identifying patients that benefit from cisplatin-based adjuvant chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC). The purpose of this study is to correlate "luminal" and "basal" type protein expression with histological subtypes, to investigate the prognostic impact on survival after adjuvant chemotherapy and to define molecular consensus subtypes of "double negative" patients (i.e., without expression of CK5/6 or GATA3).

Materials and methods: We performed immunohistochemical (IHC) analysis of CK5/6 and GATA3 for surrogate molecular subtyping in 181 MIBC samples. The mRNA expression profiles for molecular consensus classification were determined in CK5/6 and GATA3 (double) negative cases using a transcriptome panel with 19.398 mRNA targets (HTG Molecular Diagnostics). Data of 110 patients undergoing radical cystectomy were available for survival analysis.

Results: The expression of CK5/6 correlated with squamous histological subtype (96%) and expression of GATA3 was associated with micropapillary histology (100%). In the multivariate Cox-regression model, patients receiving adjuvant chemotherapy had a significant survival benefit (hazard ratio [HR]: 0.19 95% confidence interval [CI]: 0.1-0.4, p < 0.001) and double-negative cases had decreased OS (HR: 4.07; 95% CI: 1.5-10.9, p = 0.005). Double negative cases were classified as NE-like (30%), stroma-rich (30%), and Ba/Sq (40%) consensus molecular subtypes and displaying different histological subtypes.

Conclusion: Immunohistochemical-based classification was associated with histological subtypes of urothelial MIBC. IHC markers like CK5/6 and GATA3 that are used in pathological routine could help to identify patients with basal and luminal tumor characteristics. However, a two-sided classification system might not sufficiently reflect the heterogeneity of bladder cancer to make treatment decisions. Especially the group of IHC-double negative cases, as further analyzed by mRNA expression profiling, are a heterogeneous group with different implications for therapy.

Keywords: adjuvant chemotherapy; bladder cancer; consensus classification; double negative; immunohistochemistry; molecular subtyping.