The subtyping of bladder cancers is a complicated business. It is, however, necessary as it has important implications for prognosis and therapeutic decisions. CLI caught up with Asst. Prof. Chelsea L. Jackson (University of Manitoba, Winnipeg, MB, Canada) and Prof. David Berman (Queen’s University, Kingston, ON, Canada) to find out more about how the current thinking is simplifying the process.
For those of us who are unfamiliar with the details of bladder cancer, can you give us a brief overview of/introduction to the different subtypes, please?
Several research groups have revealed that similar to breast cancer, bladder cancers can be clustered into molecular subtypes with distinct biological features. These molecular subtypes are broadly classified as ‘basal-like’ or ‘luminal-like,’ corresponding to basal stem cells that reside at the basement membrane or their more differentiated progeny at the epithelial surface, respectively. Accordingly, bladder cancer subtypes represent the expression of specific urothelial differentiation programmes and tumour-cell intrinsic genomic features. The basal subtype expresses basal cell markers such as basal keratins (KRT5, KRT14), epidermal growth factor receptor (EGFR), cellular adhesion molecules (CD44, P-cadherin) and squamous epithelial programmes (DSC2/3, DSP, KRT6). Conversely, the luminal subtype expresses transcription factors that maintain a differentiated urothelial state, including transcription factors such as GATA-binding protein 3 (GATA3) and Forkhead box A1 (FOXA1). These luminal subtypes have been further divided based on their expression of specific cell-cycle regulation pathways. A ‘luminal-papillary’ or ‘urothelial-like’ (Uro) subtype is defined by active fibroblast growth factor receptor 3 (FGFR3) signalling, and losses of early cell-cycle genes such as CDKN2A. Other luminal subtypes include the ‘luminal unstable’ or ‘genomically unstable’ (GU) subtype which is defined by genomic instability, including loss of expression of tumour suppressors such as retinoblastoma (RB1), loss of cell-cycle regulation genes (e.g. Cyclin D) and FGFR3 signalling. The inclusion of other more rare subtypes may vary by study and methodology, but can include a neuroendocrine (NE) subtype and mesenchymal-like (Mes-like) subtype, which demonstrate non-urothelial histology and gene expression patterns. Subtyping schemes using RNA-based profiling techniques often report a ‘stromal-rich’ subtype and show signatures of adjacent cell types, including fibroblasts, muscle fibres, and immune cells. The luminal subtypes are well represented in the very earliest forms of bladder cancer, carcinoma in situ and low grade papillary urothelial carcinoma. Basal, NE, and Mes-like subtypes begin to manifest in high-grade invasive cancers, and herald progression of bladder cancer from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) and subsequent meta-static disease. Given their differences in cancer biology and molecular features, subtypes are believed by many to provide insights into molecular mechanisms of tumour recurrence, progression or therapy resistance.
Why is it important to diagnose bladder cancer in that detail?
As a part of an International Society for Urologic Pathology initiative, we recently worked with a group of expert pathologists, urologists, and oncologists to address this question. The resulting paper “Working Group 4: molecular subtypes of bladder cancer – principles of classification and emerging clinical utility” may be of interest to your readers as it provides a more in depth review of subtyping, the science behind it, and its potential uses [See item 4 in the Bibliography for further details]. In that paper, which also provides a number of useful references on this topic, we emphasized that despite a great deal of elegant science and progress, there are currently no clearly beneficial ways to use molecular subtyping in clinical decision-making. One of the major barriers is that studies to date have shown mixed and variable correlations between subtypes, response to therapy, and patient outcomes. As discussed below, these problems likely relate, at least in part to vagaries of mRNA profiling, where changes in
the ratio of cancer cells and benign cells can yield unstable or incorrect subtyping information. So the same cancer may be called luminal by one group and basal by another. We and others have addressed this issue by implementing subtype classification schemes based on immunohistochemistry (IHC). Studies using single cell sequencing are starting to show new and important insights into molecular subtypes.
If subtyping makes it into the clinic, it could become useful in a number of ways. The division of bladder cancers into early-stage NMIBC and more aggressive MIBC is based on the pathological stage at diagnosis. NMIBC tumours primarily present as stage pTa or pT1 tumours and represent the majority (75%) of diagnoses. Stage pTa tumours are confined to the urothelium, whereas stage pT1 tumours superficially invade the lamina propria. MIBC tumours represent only 25% of bladder cancer diagnoses, presenting as stages pT2–pT4, which are defined by invasion into the muscle layers of the bladder. Patients with NMIBC typically demonstrate a good prognosis, whereas patients with MIBC often experience a poor prognosis. Thus, the distinction between NMIBC and MIBC is critical for defining clinical management and treatment of the disease.
NMIBC is treated with local resection, sometimes followed by intravesical treatments of mitomycin C (MMC) or Bacillus-Calmette Guerin (BCG). This is followed with constant cystoscopies to monitor for recurrence or progression, which is both time consuming and expensive. Conversely, MIBCs are treated much more aggressively, with surgical removal of the bladder (cystectomy) and/or systemic therapies including radiation, chemotherapies, immunotherapies, and targeted agents. MIBCs are treated more aggressively owing to their poor survival rates. Even with the assistance of current risk classifiers, it is difficult to predict which patients will recur, progress or respond to therapies which may result in the over-treatment or under-treatment of patients. Improving risk stratification and management options for patients may rely on adding biomarkers at meaningful clinical decision-making points. For example, diagnostic biomarkers in NMIBC capable of helping a pathologist decide if a cancer is more likely to be high grade may urge the use of intra-vesical treatments and an increased cystoscopy schedule to detect recurrences or progression events earlier. In MIBC, prognostic or predictive biomarkers suggest a tumour is sensitive to chemo-therapy or may be less aggressive. Such biomarkers could allow for bladder sparing approaches to be used. Consequently, appropriate diagnosis is essential to improving treatment options for patients and also reduces costs and burden on the health care system.