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Non-Urothelial and Urothelial Variants of Bladder Cancer - Beyond the Abstract

Non-urothelial bladder cancers and urothelial variants are more challenging to diagnose and treat compared to their more common, “garden-variety” urothelial cancer (UC) counterpart owing to the rarity and aggressive nature of these cancers. Patient outcomes are generally poor when non-urothelial cancers are encountered in clinical practice1 even for those who have access to multi-disciplinary collaboration and care due to lack of high-quality, evidence-based guidelines.

In an era of cancer medicine where comprehensive genomic profiling (CGP) and targeted therapies have become increasingly commonplace, one would hope that advancements can and will be made in the treatment of rare malignancies, including non-urothelial cancers. For example, Hamman and colleagues found statistically significantly higher rates of HER2 oncoprotein expression in bladder squamous cell carcinomas (SCC) versus urothelial carcinomas (UC).2 However, patients with SCC of the genitourinary tract remain underrepresented in investigational studies of human epidermal growth factor receptor 2 (HER2) targeted therapies and their inclusion remains limited to early-phase basket trials. In contrast, several phase 2 and 3 trials investigate the use of HER2 targeted agents in typical urothelial cancers.3 Erdafitinib is a tyrosine kinase inhibitor of fibroblast growth factor (FGFR),1-4 FDA-approved for use in advanced UC with specific alterations in FGFR3 or FGFR gene fusions based on the BLC2001 study.4

Anari and colleagues reported their observations on the next-generation sequencing results performed on 72 non-urothelial bladder cancer specimens as part of their larger analysis on survival in patients with bladder SCC and adenocarcinoma. In this study, FGFR3 mutations were found in 25% of patients with bladder SCC.5 However, the BLC2001 trial excluded patients with non-urothelial genitourinary tract cancers, and to date, the role of erdafitinib in FGFR mutated non-urothelial or variant bladder cancers is unknown. Nectin-4 and Trop-2 are variably expressed in SCCs and adenocarcinomas of the bladder, as in typical UCs.6 Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates that target Nectin-4 and Trop-2, respectively, and are both FDA-approved for use in metastatic UC, but they have not been formally evaluated in non-urothelial cancers, including SCC and adenocarcinoma.7 PD-L1 expression and microsatellite instability have also been variably noted in non-urothelial bladder tumors, but their predictive value with regard to response to immune checkpoint inhibitors in this particular patient population remains unclear.

As evidenced by the aforementioned studies, some non-urothelial GU tract histologies may bear some resemblance to typical UC on a genomic and molecular level. Several novel agents already approved for use in advanced UC in recent years, as well as other targeted therapies on the horizon, may very well be relevant in the management of rare GU tract cancers, which remains an area of unmet need. It is imperative to consider the inclusion of patients with non-urothelial and variant-predominant urothelial cancers of the GU tract in larger prospective interventional trials and to pursue further study of GU tumor-agnostic therapies based on genomic and molecular characteristics.

Written by: Eun-mi Yu, MD & Jeanny B. Aragon-Ching MD, FACP, GU Medical Oncology, Inova Schar Cancer Institute, Fairfax, VA

References:

  1. Aragon-Ching JB, Wang H: Contemporary treatment and survival differences in patients with urothelial versus nonurothelial bladder and upper tract carcinomas: Analyses from the National Cancer Database (NCDB). Journal of Clinical Oncology 40:463-463, 2022
  2. Hammam O, Nour HH, Mosaad M, et al: The clinical significance of HER2 protein amplification/expression in urinary bladder lesion. Arab J Urol 13:146-52, 2015
  3. Shi F, Liu Y, Zhou X, et al: Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy. Drug Deliv 29:1335-1344, 2022
  4. Loriot Y, Necchi A, Park SH, et al: Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 381:338-348, 2019
  5. Anari F, Miron B, Henson D, et al: Non-urothelial bladder cancer: Genomic alterations and patient outcomes. Journal of Clinical Oncology 37:399-399, 2019
  6. Wucherpfennig S, Rose M, Maurer A, et al: Evaluation of Therapeutic Targets in Histological Subtypes of Bladder Cancer. Int J Mol Sci 22, 2021
  7. Koshkin VS, Osbourne AS, Grivas P: Treatment options for advanced urothelial cancer after progression on chemotherapy and immune checkpoint inhibitors: a literature review. Transl Androl Urol 10:4022-4035, 2021

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