Targeted therapies in the treatment of urothelial cancers: Beyond the Abstract

Metastatic urothelial cancers are aggressive neoplasms for which treatment poses an increased unmet medical need.  For several decades, there have been no satisfactory drug approvals and patients unfortunately succumb to the disease after first-line platinum-based containing chemotherapy.  In addition, given the population that is frequently afflicted with this disease, ability to tolerate platinum-based combination therapies is also often limited.  There is an ever growing interest in using targeted therapies as a treatment for urothelial cancers. 

The Cancer Genome Atlas (TCGA)1  has shed light on various molecular subtypes of bladder cancer, similar to that described in breast cancer.   There are varying cluster types with cluster I frequently represented as a papillary cluster, with frequent activating FGFR3 mutations, similar to what would be considered as superficial bladder cancers.  Clusters I and II also have frequent human epidermal growth factor 2 (HER2) expression  although described also as “p-53-like” in another whole-genome sequencing group from the MD Anderson, while cluster III showed high expression of epithelial markers and half showed p53 mutations.  Cluster IV  is similar to that of claudin-low in breast cancers which have high metastatic potential.   Given the varying pathways involved, targeted therapies using vascular endothelial growth factor (VEGFR) inhibitors such as bevacizumab and ramucirumab, have been shown to have promising results.  

However, there are other trials that also showed disappointingly negative results, such as pazopanib in the PLUTO trial.3 Other pathways that target the human epidermal growth factor family, HER-2 and EGFR, have also been studied.  One of the most promising pathways includes that of fibroblast growth factor receptor (FGFR) inhibitors.  Varying clinical trials that use targeted molecular pathways as a means of directing treatment are also underway.  Similarly, the possibility of sequential or combination treatment with either chemotherapy or use of immunotherapy are attractive options in the overall treatment landscape.   This article describes further the ongoing treatment trials that utilizes these targeted agents in advanced or metastatic urothelial cancers.4

Written By: Jeanny Aragon-Ching, M.D., F.A.C.P., Clinical Program Director of Genitourinary Cancers, Inova Schar Cancer Institute, Fairfax, VA

References:
  1. Comprehensive molecular characterization of urothelial bladder carcinoma.  The TCGA. Nature 2014 (507): 315–322.
  2. McConkey D, Choi W, and Dinney CL. New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician.  Eur Urol. 2014: 609-10.
  3. Jones RJ, Hussain SA, Protheroe AS, et al.  Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer.   J Clin Oncol.  2017, DOI: 10.1200/JCO.2016.70.7828.  [Epub ahead of print].  
  4. Aragon-Ching JB and Trump DL. Targeted therapies in the treatment of urothelial cancers.  Urol Oncol. 2017 Mar 30. pii: S1078-1439(17)30111-4. DOI: 10.1016/j.urolonc.2017.03.011. [Epub ahead of print]

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