In the United States, the annual incidence of bladder cancer is 81,400 patients with 17,980 annual deaths.1 The majority of bladder cancers originate from the urothelium, with the most important initial risk stratification decision made for these cancers based on whether it is invasive or non-invasive, and how deeply it has invaded if invasive.2 In patients who do not have evidence of metastasis at the time of diagnosis, these guidelines recommend considering a number of possible treatment approaches of varying intensity and invasiveness, often with recommended follow-up and potential escalation of therapy when there is persistent evidence of cancer. For clinical non-invasive papillary urothelial carcinoma potential treatment approaches include intravesical Bacillus Calmette-Guerin (BCG), intravesical chemotherapy, or even observation13. For clinical T1 tumors, potential treatment options include either transurethral resection of the bladder tumor (TURBT) or cystectomy. In patients with stage II or stage IIIa disease, potential treatment options include chemotherapy, radiation, chemoradiation, and surgery accompanied possibly by neoadjuvant and/or adjuvant chemotherapy13. While guidelines base recommendations for treatment of localized urothelial cancers heavily on risk stratification, within individual risk groups, the guidelines recommend consideration of multiple treatment strategies of varying levels in intensity and known significant side effects within individual strata. Risk stratification for treatment decisions in patients who are not having or have not yet had a cystectomy are based on clinical staging information; evidence has shown that changes in staging based on pathologic information following cystectomy are common, altering disease risk.3 For example, in advanced bladder cancer, fibroblast growth factor receptor 3 (FGFR3) and fibroblast growth factor receptor 2 (FGFR2) mutations have also been found to be associated with response to erdafitinib, which has been Food and Drug Administration (FDA) approved for use in bladder cancer with FGFR3 and FGFR2 mutations.4
Among the non-urothelial bladder cancers, squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors have been recognized as important for implications concerning treatment.2 Current recommendations do not suggest chemotherapy for pure squamous or adenocarcinoma of the bladder with radiotherapy and/or surgical resection being the mainstays of treatment.2 Neuroendocrine and neuroendocrine-like tumors and those tumors with small cell features have been recognized to be a poor prognostic subtype for which aggressive treatment is recommended regardless of stage including chemotherapy and possibly cystectomy and radiotherapy.2 The diagnosis of neuroendocrine (NE) and neuroendocrine-like tumors in the bladder may be challenging, particularly on histology alone, and therefore often requires use of additional diagnostic information, such as special stains to look for neuroendocrine features.5,6
With current standards of care, patients diagnosed with bladder cancer have 5-year relative survival rates (compared to peers without bladder cancer) of 95.8% in cases of in-situ carcinoma and 69.5% in cases of localized cancer with absolute survival rates of 51% and 34% for in-situ and local disease respectively.7
Molecular subtyping has emerged as a potential diagnostic aid in bladder cancer both to help identify the type of bladder cancer and to more accurately assess the risk and benefit profile of various treatment approaches and to aid in the diagnosis of bladder cancer subtype and risk.
Ross and colleagues looked at a comprehensive genomic profile (CGP) of 295 cases of advanced urothelial carcinoma and were able to demonstrate that over 90% had at least 1 clinically relevant genetic alteration per each separate case. The most common clinically relevant genetic alterations were cyclin dependent kinase inhibitor 2A (CDKN2A), FGFR3, phosphatidylinositol 3 kinase catalytic subunit alpha (PIK3CA) and erythroblastic oncogene B2 (ERBB2).14
Seiler and colleagues developed and validated an algorithm that predicts outcomes in urothelial carcinoma based on molecular subtyping using an algorithm based on gene expression data.8 The algorithm classified bladder cancer into 1 of 4 subtypes: Claudin-low, basal, luminal-infiltrated, and luminal. They found that the algorithm also predicted response to neoadjuvant chemotherapy. Luminal tumors (non-infiltrated) demonstrated a comparatively good prognosis that appeared minimally affected by differences between patients who did and did not receive neoadjuvant therapy. Basal tumors demonstrated a poor prognosis without neoadjuvant therapy. The prognosis was significantly improved with neoadjuvant therapy to be similar to luminal tumors. The same subtyping algorithm was evaluated in bladder cancers pre-cystectomy as a predictor of pathologic upstaging.9 Consistent with Seiler’s work showing better prognoses for luminal tumors, it was found that luminal tumors were less likely to be upstaged. Gene expression data has also been found to identify NE-like bladder cancers that histologically appear like urothelial carcinomas. 10