The molecular biomarkers and pathways involved in UC are key to understanding its biological heterogeneity and identifying specific subtypes, which may be used to predict treatment outcomes.[5] In other words, knowing the molecular subtype of a given UC could help predict the clinical outcomes and treatment benefits for patients.[5][6]
What’s more, understanding the molecular subtypes of bladder cancer can help reveal potential biomarkers, identify distinct patient subpopulations and inform treatment decision-making.[5][6]
Some of the emerging, potentially predictive biomarkers for UC include:
> FGFR alterations
> PD-(L)1 expression
> Tumour mutational burden
> Tumour microenvironment
> Other molecular signatures
A detailed molecular understanding of UC has resulted in the identification of distinct subtypes that could help guide treatment approaches.[6] For example, molecular subtypes of MIBC have been associated with different responses to treatments such as chemotherapy or immunotherapy.[6][12][13]
More specifically, recent developments in our understanding of the pathology of bladder cancer have led to the identification of six molecular classes. In descending order of prevalence, the six subtypes of MIBC are:[6]
Basal/squamous (35%)
Stroma-rich (15%)
Luminal papillary (24%)
Luminal non-specified (8%)
Luminal unstable (15%)
Neuroendocrine-like (3%)
As shown in the table below, each molecular subtype of MIBC has distinct:[6]
> Differentiation patterns (e.g. urothelial/luminal, basal or neuroendocrine)
> Oncogenic mechanisms (e.g. FGFR3, PPARG, RB1, etc.)
> Tumour microenvironments (e.g. stromal or immune infiltration)
> Histological characteristics (e.g. papillary, squamous or neuroendocrine)
> Clinical associations (e.g. tumour stage, sex or age)
Adapted from Kamoun A et al. 2020.[6]
A bladder cancer patient’s chance of survival is highly stage-dependent, and progression from MIBC to metastasis is common[15][16][17]
Despite guideline-recommended radical cystectomy, up to 50% of patients with MIBC may experience distant recurrence.[18]
Additionally, systemic recurrence is more common in locally advanced disease (ranging from 32-62%) as well as in patients with lymph node involvement (ranging from 52-70%).[18]
The treatment approach in LA/mUC remains controversial, with evidence about some areas of bladder cancer management being limited and/or conflicting[19]
The treatment landscape for bladder cancer is beginning to experience a paradigm shift towards the use of targeted therapy, owing to the following:[5][20]
> a better understanding of the molecular and genetic heterogeneity of tumour types
> the investigation of molecular signatures predicting disease progression and therapeutic response
> the discovery and implementation of tailored therapies
However, molecular biomarkers are not commonly used in routine clinical practice for LA/mUC patient care.[8][21]
Understanding the genomic alterations that can drive tumour growth has improved patient outcomes across cancer types.[10][14] As a consequence, international guidelines recommend the routine use of molecular testing in advanced or metastatic tumours, owing to its potential benefits for oncology patient care.[11][23]
The management of UC is increasingly becoming multidisciplinary, with close cooperation and critical input needed from different specialities to inform effective disease management plans for patients.[18][26]
Work with your pathologist now to set up a testing infrastructure and/or ensure your testing capabilities cater to the advancement of biomarker-led precision medicine for your LA/mUC patients[27]
When establishing molecular testing protocols for your LA/mUC patients, it is important to liaise with the treating urologist to ensure sufficient sample quality is available[25]
APOBEC: apolipoprotein B mRNA editing catalytic polypeptide-like; CD8 T cells: cytotoxic T lymphocytes; CDKN2A: cyclin-dependent kinase inhibitor 2A; DNA: deoxyribonucleic acid; E2F3: gene encoding E2F transcription factor 3; EGFR: epidermal growth factor receptor; ELF3: gene encoding E74-like ETS transcription factor 3; ERBB2: gene encoding receptor tyrosine-protein kinase erbB-2; ERCC2: gene encoding XPD protein; ESMO: European Society of Medical Oncology; FFPE: formalin fixed paraffin embedded; FGFR: fibroblast growth factor receptor; KDM6A: gene encoding lysine-specific demethylase 6A; LA: locally advanced; MDT: multidisciplinary team; MIBC: muscle-invasive bladder cancer; mUC: metastatic UC; NCCN®: National Comprehensive Cancer Network®; NGS: next-generation sequencing; NK cells: natural killer cells; PD-(L)1: programmed death-ligand 1; PPARG: peroxisome proliferator-activated receptor gamma; RB1: gene encoding tumour suppressor retinoblastoma protein 1; T2: tumour growth into muscle; T3: tumour growth into fat layer; T4: tumour growth outside of the bladder; TMB: tumour mutational burden; TP53: gene encodes p53; UC: urothelial carcinoma.