Performance of IHC3-Uro Immunohistochemistry-based Molecular Subtyping in Muscle-Invasive Bladder Cancer

Abstract

Molecular subtyping in muscle-invasive bladder cancer (MIBC) has shown important relationships to both prognosis and chemosensitivity. However, insufficient validation and complex testing methods have prevented molecular subtyping from being clinically implemented. To address these shortcomings, 13 immunohistochemistry (IHC) assays were previously validated to identify Three key intrinsic subtypes of MIBC. We distilled this work into a three-antibody algorithm termed IHC3-Uro which uses GATA3, p16 and KRT5 to identify key IHC-based subtypes in MIBC. If effective in determining subtype, this simple IHC-based test could serve as a useful tool in pathologic practice to guide clinical decision making. We applied IHC3-Uro to three independent MIBC cohorts in order to identify molecular subtypes and explore their relationships to clinicopathologic variables and outcomes. In this work, 89% of samples were assigned to Uro, GU and Basal intrinsic molecular subtypes. This subtyping appeared to be the most effective in TURBT samples, where GATA3 staining was most consistent. These subtypes showed prognostic associations, where the GU subtype and a subset of Uro tumours termed Uro-KRT5 had increased risk of death compared to the Uro subtype. Altogether, this work suggests that a simple IHC-based test may serve as an effective alternative for identifying prognostically relevant subtypes previously discovered using complex transcriptomic methods. Additional validation and investigation of these IHC-based subtypes may provide opportunities for clinical use and optimizing patient stratification according to risk of death.