Impact of immunohistochemistry-based subtyping of GATA3, CK20, CK5/6, and CK14 expression on survival after radical cystectomy for muscle-invasive bladder cancer

Abstract

Molecular subtyping of muscle-invasive bladder cancer (MIBC) predicts disease progression and treatment response. However, standard subtyping based on transcriptomic analysis is relatively expensive. This study tried to use immunohistochemistry (IHC) to subtype MIBC based on GATA3, CK20, CK5/6, and CK14 protein expression. The IHC-based subtypes in MIBC subtypes were classified as luminal (GATA3+ CK5/6−, 38.6%), basal (GATA3−CK5/6+, 12.9%), mixed (GATA3+ CK5/6+, 37.9%), and double-negative (GATA3−CK5/6−, 10.6%) in 132 MIBC patients. All individual markers and clinicopathological parameters were analyzed against treatment outcomes after radical cystectomy. The mean patient age was 65.6 years, and the male to female ratio was 6.8:1. Positive IHC expression of GATA3, CK20, CK5/6, and CK14 were 80.3%, 50.8%, 42.4%, and 28.0%, respectively. Only GATA3 and CK5/6 were significantly associated with survival outcome (p values = 0.004 and 0.02). The mixed subtype was significantly better in 5-year OS at 42.8%, whereas the double-negative subtype had the worst prognosis (5-year OS 7.14%). The double-negative subtype had a hazard ratio of 3.29 (95% CI 1.71–6.32). Subtyping using GATA3 and CK5/6 was applicable in MIBCs, and patients with the double-negative subtype were at the highest risk and may require more intensive therapy.

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

“…The cohort seems to be of biological significance, as patients in this group had an increased risk of death in multivariate analysis. This finding has recently been described also by other groups ( 13 , 14 ). However, no detailed molecular analyses were reported, as no full transcriptomic analyses were performed ( 12 , 13 ).…”

“…To facilitate the clinical implementation of subtyping into clinical routine, immunohistochemical (IHC) markers that refer to “basal” and “luminal” molecular subtypes have been proposed ( 12 – 14 ). Guo et al reported that IHC-staining with GATA3 and CK5/6 can classify the BCa correctly in over 80% of the cases into luminal and basal molecular subtypes.…”

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

“…The DN subtype accounted for approximately 10% of cases in the study by Bejrananda et al and was associated with the worst 5-year overall survival (OS), with a hazard ratio as high as 3.29 [ 30 ]. Accordingly, CK5−/CK20− DN tumors were as many as 13% in the study by Al-Sharaky et al [ 36 ].…”

GATA3 Predicts the Tumor Microenvironment Phenotypes and Molecular Subtypes for Bladder Carcinoma

“…Although GATA3 is highly expressed in bladder cancer, its high expression may adversely inhibit the progression of tumor cells in BLCA ( 6 ). Meanwhile, the over-expression of GATA3 predicts a lower tumor stage and a lower tumor grade but a higher relapse-free survival rate ( 7 , 8 ). Such an imbalance between the over-expression profile of GATA3 in BLCA cancer tissues and the inhibitory function of GATA3 on bladder cancer cells may be explained by the ability of GATA3 to transform basal bladder cancer cells into luminal cells ( 7 , 9 , 10 ).…”

“…Meanwhile, the over-expression of GATA3 predicts a lower tumor stage and a lower tumor grade but a higher relapse-free survival rate ( 7 , 8 ). Such an imbalance between the over-expression profile of GATA3 in BLCA cancer tissues and the inhibitory function of GATA3 on bladder cancer cells may be explained by the ability of GATA3 to transform basal bladder cancer cells into luminal cells ( 7 , 9 , 10 ). Universally, the basal bladder cancer subtypes had a poorer prognosis compared with the luminal bladder cancer subtypes ( 11 , 12 ).…”