SIU 2017: Can Genetic Analysis in Bladder Cancer Enhance Decision Making

Lisbon, Portugal (UroToday.com) Dr. Black started his presentation by saying that the answer to the title question is “yes (maybe)”. The data is beginning to demonstrate that, but its not quite sufficient enough change in management on a larger scale.

 While there is a lot of data to support the use of NAC, there are two major gaps in its widespread utilization:

  1. Only 40% of patients have major response to chemotherapy
  2. NAC is not widely used in most parts of the world
The best response to these gaps in care is better risk stratification and patient selection for chemotherapy response, with the use of biomarkers.

Three different molecular markers to discuss:
  1. Molecular subtypes
  2. COXEN model
  3. Genomic alterations
Molecular Subtypes

  • Refer to Dr. Lerner’s talk for most recent update on the 5 molecular subtypes – but broadly separated into luminal and basal subtype
  • Subtype is associated with response to chemotherapy
           o   Basal tumor respond very well
           o   P53 like tumors respond poorly

  • Dr. Black worked with Genome Dx to generate a genomic test that could classify a patient sitting in front of you in clinic into 1 of 4 molecular classes
           o   Using discovery and validation set, proved that basal molecular subtypes are the best responders to NAC cisplatin
           o   Luminal tumors do well regardless of NAC

COXEN Model “Coexpression Extrapolation”

  • Being developed based on 60 cell lines and their drug response
  • Test a patient’s gene expression against the pool of cell line data to determine the best “match”
  • Shown an accuracy ~80%
  • Currently in a prospective study with SWOG – will finish accrual by the end of the year
Genomic Alterations
  • Individual Gene alterations, particularly DNA repair genes
  • Will likely gain more recognition as predictors of response
  • I.e. ERCC2 gene alterations were found only in patients with chemotherapy response – validated in a second cohort in FCCC
           o   Therefore those patients with ERCC2 mutations treated with chemotherapy do well

  • Mutations in ATM, Rb1, FANC – 3 gene panel
           o   Patients with mutation in at least one of these genes had a high rate of response to chemotherapy

  • ERBB2 (Her2) 
           o   Predictive of chemotherapy response, but not yet validated

There is a lot of good work working to help strengthen the risk stratification of patients prior to NAC. By doing so, utilization in appropriate patients may increase and patients that wouldn’t have responded to NAC can go straight to RC or targeted therapy.

Presented by: Peter Black

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal
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