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 . 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 . 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
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