Non-muscle invasive bladder cancer biomarkers beyond morphology

Abstract

Non-muscle invasive bladder cancer (NMIBC) still represents a challenge in decision-making and clinical management since prognostic and predictive biomarkers of response to treatment are still under investigation. In addition to the risk factors defined by EORTC guidelines, histological features have also been considered key variables able to impact on recurrence and progression in bladder cancer. Conversely, the role of genomic rearrangements or expression of specific proteins at tissue level need further assessment in NMIBC. As with muscle-invasive cancer, NMIBC is a heterogeneous disease, characterized by genomic instability, varying rates of mutation and a wide range of protein tissue expression. In this Review, we summarized the recent evidence on prognostic and predictive tissue biomarkers in NMIBC, beyond morphological parameters, outlining how they could affect tumor biology and consequently its behavior during clinical care. Our aim was to facilitate clinical evaluation of promising biomarkers that may be employed to better stratify patients. We described the most common molecular events and immunohistochemical protein expressions linked to recurrence and progression. Moreover, we discussed the link between available treatments and molecular drivers that could be predictive of clinical response. In conclusion, we foster further investigations with particular focus on immunohistochemical evaluation of tissue biomarkers, a promising and cost-effective tool for daily practice.

Keywords: BCG response; biomarker; bladder cancer; molecular subtypes; non-muscle invasive bladder cancer; predictive; prognostic.

Figure 1

Overall estimation of the possible impact on clinical outcome of the main prognostic biomarkers expression or overexpression in NMIBC. Despite the highlighted conflicting results, it is possible to identify a tendency of the markers to be reported as predictors of better (blue) or worse (yellow) outcome in the literature. For other markers this simplification is not possible (in the middle).The size of the markers graphically reflects the number of studies investigating their prognostic role in NMIBC. AR, androgen receptor; COX-2, Cyclooxygenase-2; FGFR3, fibroblast growth factor receptor 3; HER-2, human epidermal growth factor receptor 2; TILs, tumor-infiltrating lymphocytes.

Figure 2

Molecular phenotyping with immunohistochemistry in NMIBC. A prototypical example of Luminal type urothelial carcinoma (UC) with the Luminal marker CK20 (A) expressed in almost all tumor cells; in contrast, the Basal marker CD44 is limited to the basal layer (B). Conversely, a typical Basal type UC showing negativity for CK20 (C) and diffuse CD44 expression (D).

Figure 3

Impact of the predictive biomarkers on the clinical outcome in NMIBC. Markers improving the tumor outcome (A) during treatment with BCG (bacillus Calmette-Guérin), MMC (mitomycin C) or TKIs (tyrosine kinase inhibitors). Markers worsening the tumor outcome (B) during treatment with BCG or GEM (Gemcitabine). FGFR3, fibroblast growth factor receptor 3; FGFR1-4, fibroblast epidermal growth factor receptor 1-4; CD4/CD8, CD4/CD8 T-Lymphocytes; GATA-3, GATA binding protein 3; TMB, Tumor Mutational Burden; Th-2, T helper-2 lymphocytes; ICD, mitochondria-mediated immunogenic cell death; FOXM1, Forkhead Box M1; RRM-1, ribonucleotide reductase subunit M1; PD1-PD-L1, Programmed Cell Death Protein 1/Programmed death-ligand 1; Th-1, T helper-1 lymphocytes; ARID1a, AT-rich interactive domain-containing protein 1A.