Summary | Case Presentation: 58 year old man, 20 pack-year smoking history, healthy (hypertension), presents with one-time gross hematuria. White light cysto – solitary papillary tumor on left side. Cytology – high grade. Upper tract evaluation normal. No family history.
PDD + TURBT – pT1 HG TCC
Re-TURBT at 4 weeks – pT0
Undergoes BCG induction. Develops a recurrence. Appears invasive, T2 disease. His question was the impact of molecular characterization. Does it impact treatment?
Discussant 1: D. McKonkey
Obviously, Dr. McKonkey argued that molecular characterization matters. However, as usual, he clarified saying that it is not yet ready for clinical practice until prospective trials establish its utility!
1. Neoadjuvant chemotherapy – while is has demonstrable modest effect on patients with MIBC, not every patient benefits. Those that don’t, have a delay to their definitive therapy: RC.
- Molecular subtype can help select appropriate patients
- Seiler et al EU 2017 – patients with basal type MIBC appear to have the greatest benefit from NAC, albeit in a retrospective analysis
- DNA damage and repair mutations are also linked to chemosensitivity
- MSKCC: ERCC2 mutations
- FCCC (Fox Chase, Plimack): RB1, ATM, FANCC mutations
2. Immune checkpoint blockade
- Neoantigen load, total mutational burden are potential biomarkers of response to immune checkpoint blockade
- Immune signatures are potential predictors (being evaluated)
- Molecular subtypes are potential predictors (being evaluated)
- Papillary (luminal) tumors had the lowest response rates (Rosenberg et al, ASCO 2016)
Discussant 2: J. Bellmunt
Dr. Bellmunt argued the opposing view. First, he notes that the TCGA data is from MIBC, not NMIBC. Hence, it is not as applicable to this patient’s situation. Also, most of the data from NMIBC is from LG tumors, so not applicable to this patient. There is also a lack of good recurrence and progression data for NMIBC, so makes it difficult to make any conclusions for this patient. He then reviewed the genetic changes between MIBC and NMIBC, highlighting that these are two very different genetic conditions. There are a few studies that have looked at genetic predictors / prognostic indices for NMIBC.
- Dryskjot L aet al, EU 2017 - 12 gene progression risk in NMIBC
- High progression score associated with high age, high stage, concomitant CIS, BCG treatment, progression to MIBC, and high EORTC risk calculation
- Associated with previously identified molecular classes in NMIBC
- Combined with EORTC risk calculator, very promising!
- Van der Heijden et al EJC – 5 gene signature to predict progression
- Identified a 5-gene signature to predict progression in T1 HG TCC
- Predicts which patients are at higher risk of progression
- Pietzak EJ EU 2017 – Next gen sequencing of NMIBC
- ERBB2 and FGR3 mutations present in 57% of HG NMIBC tumors
- DDR alterations seen in 30%of tumors
- ARID1A mutations associated with increased risk of recurrence after BCG
Presented by: A. Stenzl
Discussants: J. Bellmunt, and D. McKonkey
Written by: Thenappan Chandrasekar, MD Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark