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CK5/6 and GATA3 for Phenotyping Subtypes of Bladder Cancer - Expert Commentary

Predicting response to adjuvant therapy in patients with bladder cancer has the potential to prevent needless toxicity and optimize efficacy. In recent years, transcriptomic studies of bladder cancer tissues have identified molecular subtypes that exhibit differential responses to different treatment types. Two markers that can accurately differentiate between basal and luminal molecular subtypes are GATA3 and CK5/6. However, tumors that lack expression of both these markers (double negative cases) are still not well understood. Koll et al. validated the use of these markers for subtyping and their association with survival and performed RNA-sequencing of double negative samples to characterize them further.

Koll et al. collected tissue samples and patient data from 181 muscle-invasive bladder cancer patients treated at the University Cancer Center Frankfurt between 2010 and 2020. First, these samples were classified into subtypes based on the expression of CK5/6 and GATA3. CK5/6 positive cases were correlated with the female gender and squamous histological subtypes. All neuroendocrine subtypes were double negative for CK5/6 and GATA3.

Among a subset of 110 patients who received radical cystectomy, neither marker expression nor histological subtype was associated with overall survival or disease-free survival. Using a multivariate Cox-regression model adjusting for tumor and lymph node (LN) stage, adjuvant chemotherapy, and IHC-staining, the investigators found that 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). Next, Koll et al. analyzed ten double negative cases and found that three of these were stroma-rich, three were neuroendocrine-like, and four were basal/squamous. Basal/squamous samples displayed heterogeneity of histological patterns. Double negative cases had a higher risk of death.

While these findings emphasize the prognostic and predictive value of performing immunohistochemistry to characterize CK5/6 and GATA3, they also reveal the complexity of double negative cases that limit the possibility of using a two-tailed classification system. This is partly due to the extensive heterogeneity of double-negative tumors. One limitation of this study is the small number of double negative cases. Accordingly, in-depth studies on these cases and immunohistochemical screening will be essential for identifying alternative prognostic biomarkers. Data on the predictive accuracy of CK5/6 and GATA3 as predictors of benefit from chemotherapy are still emerging. Further research is needed to consolidate their validity, considering the biology of the underlying subtypes and the various subtyping methods.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Koll FJ, Schwarz A, Köllermann J, et al. 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;9:875142. Published 2022 Jun 16. doi:10.3389/fmed.2022.875142

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