EAU 2018: Molecular and Histopathological Heterogeneity in Muscle-Invasive Bladder Cancer

Copenhagen, Denmark (UroToday.com) Dr. Antonio Lopez-Beltran from Spain gave a talk on molecular and histopathological heterogeneity in muscle invasive bladder cancer (MIBC). Dr. Lopez-Beltran started by highlighting that urothelial carcinoma has two morphologic and molecular phenotypes: non-muscle invasive bladder cancer (NMIBC; 70-80%) and MIBC (20-30%). 

Mutations/alterations common in bladder cancer include HRAS-activating mutation, FGFR3-activating mutation, p53 alteration, p21 alteration, Rb alteration, and p16 alteration. In a landmark Nature study from 2014, among 131 MIBC patients integrated genomic analysis was performed [1]. The average genetic alterations per tumor was 302 mutations, 204 segmental CNA, and 22 rearrangements. Recurrent mutations in 32 genes included cell-cycle regulation, chromatin regulation, and RTK signaling pathways. Importantly, these mutations/alterations resulted in potential targeted therapies for 69% of patients, including mTOR/PIK3CA, RTK/MAPK (ERBB2), and ER. 

A new genomic taxonomy has emerged with recent analyses of the TCGA dataset. This is related to integrated gene expression subtypes, including papillary-like, basal and luminal. Luminal MIBCs are typically chemo-resistant, with possible targeted therapy for mTOR, PI3K, and IGFR-1. Basal MIBCs have the potential for checkpoint inhibitors and chemotherapy. Further evidence of bladder cancer heterogeneity is suggested by a variant histology rate of ~20%.  One of the more common variant histologies is diffuse/plasmacytoid variant, which has been shown to frequent somatic CDH1 loss-of-function mutations. In a study of 31 patients with plasmacytoid variant histology, median survival was only 17.7 months from diagnosis [2]. Despite pathologic downstaging among 80% of patients undergoing neoadjuvant chemotherapy, relapses were common and there was no survival difference between patients undergoing neoadjuvant chemotherapy and those undergoing upfront radical cystectomy. 

Dr. Lopez-Beltran concluded with several take-home messages:

  • Urothelial carcinoma is a highly heterogeneous disease at both the histologic and molecular levels
  • There is potential for reporting molecular subtypes using immunohistochemistry with cytokeratins as a surrogate of molecular alterations
  • Immunohistochemistry can be applied to urothelial carcinoma with pure histology and urothelial carcinoma with variant histology
  • The potential framework to advance in bladder cancer research prospectively is in place, but a joint effort is needed between urologic oncologists, basic scientists and pathologists
References:
1. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507(7492):315-322.
2. Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. J Urol 2013;189(5):1656-1661.


Presented by: Antonio Lopez-Beltran, Spain and Champalimaud Clinical Center, Lisbon, Portugal

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark
E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe