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SIU 2018: Interpretation and Clinical Implication of Cancer Genetics in Uro-Oncology -Bladder Cancer

Seoul, South-Korea (UroToday.com) Dr. Agarwal provides a nice summary of the current status of the rapidly advancing landscape of bladder cancer genomics. He starts by describing our initial concept of a dual pathway in bladder cancer – depicted below. In this model, normal urothelium has 2 pathways – either development of FGFR3 mutations and progression to low-grade low risk bladder cancer OR development of P53, Rb, etc. mutations leading to high-grade disease, CIS and invasive bladder cancer.

Dual pathway in bladder cancer

This was the extent of our knowledge until just a few years ago. But, in 2013 (Beijing Genomics Institute, Guo et al. Nat Genet 2013) and 2014 (TCGA Network, Nature 2014), the landscape completed changed. These 2 major studies, followed by other large genomic studies, identified large percentage of chromatic remodeling genetic mutations (60-80%) and lead to an establishment of the framework of molecular grades/classes. 

In 2017, the TCGA updated its analysis (Robinson et al. Cell 2017) – an increase from 131 to 412 MIBC samples resulted in new findings, specifically an addition of a 5th molecular class (neuroendocrine) with very poor prognosis, 69% of samples with actionable targets, and an overall mutational load associated with APOBEC gene signature.

There has been a lot of work on molecular subtypes in MIBC. As of right now, there are multiple different names schemes, but they all have similar overlaps. He reviewed the 5 TCGA subtypes – luminal, luminal-infiltrated, luminal-papillary, basal, neuronal. 

Next, he began to explore the association between mutational load, mutational signature, molecular subtype and outcomes. 
  • Higher Mutational burden, higher mutation load, higher APOBEC mutation load and higher neoantigen load were all associated with BETTER overall survival in the TCGA 2017 data analysis
  • Molecular subtypes, as previously discussed, were also associated with survival outcomes
How does this relate to treatment response?
  • Rosenberg et al. Lancet 2016 – Luminal-infiltrated subtype and mutational load independently predicted anti-PD-L1 response
  • Multiple studies (Van Allen Cancer Disc 2014, Plimack EU 2015, etc.) – Mutations in ERBB2/ERCC2 and DNA damage response genes predict chemotherapy sensitivity (all enriched in neoadjuvant chemotherapy responders)
  • A theoretical model provided in the Robertson data highlights how molecular subtype may drive treatment:
Potential Targets Identified by TCGA
  • Seiler et al – molecular subtypes predict NAC sensitivity
  • Patients with luminal subtype did well, regardless of NAC or not
  • Patients with basal subtype did poorly, but seemed to have a strong improvement with NAC
Some of this work in MIBC is getting translated over into the NMIBC (non-muscle invasive bladder cancer) arena. 
  • Pietzak et al. EU 2018 and Knowles et al. Cancer
  • High prevalence of TERT promoter mutations and chromatin remodeling genes
  • DNA repair genes seen in 30% of high-grade NMIBC
  • Certain groups (Descotes Br J Cancer 2017) have started to look at urine markers for NMIBC as well
Lastly, he briefly touched on germline mutations for bladder cancer. This is much less developed than for prostate cancer.
  • Patients with upper tract urothelial cancer or early-age bladder cancer should be considered for genetic testing
  • Mark et al. J Urol 2015 – 22% of 113 patients found to have a germline mutation, 58% of those in DDR genes, mutations were highly penetrant
This was a great succinct overview of this topic – this is rapidly changing and advancing, more than for any other GU malignancy. It has significant potential, but a lot of work to be done still!

Presented by: Piyush Agarwal, United States

References: 
1. Beijing Genomics Institute, Guo et al. Nat Genet 2013
2. TCGA Network, Nature 2014
3. Robinson et al. Cell 2017
4. Rosenberg et al. Lancet 2016
5. Van Allen Cancer Disc 2014,
6. Plimack EU 2015, 
7. Descotes Br J Cancer 2017

Written By: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University Twitter: @tchandra_uromd, @TjuUrology at the 38th Congress of the Society of International Urology - October 4- 7, 2018 - Seoul, South Korea