Summary | Case Presentation: 52 year old man, former smoker. Gross hematuria while jogging. CT scan with bladder mass, otherwise normal. TURBT of a 4 cm sessile bladder tumor, EUA benign, Pathology: MIBC, Recommendation: NAC + RC
However, he is an engineer. Well educated. He had appropriate questions re:
1) Should he receive NAC or go straight to cystectomy? Modest benefit, significant side effects.
2) Can molecular testing inform his decision?
Discussant 1: P. Black
Dr. Black argued yes for both. However, he noted that molecular testing is not yet approved and prospectively validated, but may be in the next few years.
While there is a lot of data to support the use of NAC, there are two major gaps in its widespread utilization:
- Only 40% of patients have major response to chemotherapy
- 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: Molecular subtypes, COXEN model, Genomic alterations, Molecular Subtypes
There are numerous recent studies focusing on the 5 molecular subtypes – but broadly separated into luminal and basal subtype. Subtype is associated with response to chemotherapy
- Basal tumor respond very well
- P53 like tumors respond poorly
- Using discovery and validation set, proved that basal molecular subtypes are the best responders to NAC cisplatin (in a retrospective analysis)
- Luminal tumors do well regardless of NAC
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
- Therefore those patients with ERCC2 mutations treated with chemotherapy do well
- Patients with mutation in at least one of these genes had a high rate of response to chemotherapy
- Predictive of chemotherapy response, but not yet validated
Discussant 2: J. Bellmunt
Dr. Bellmunt notes that while there has always been a skepticism towards the 7% survival benefit of NAC prior to RC, similar results for chemotherapy in breast cancer have never been questioned – it is guideline recommendation and should be offered to all eligible patients!
Even in patients with pT2 tumors (rather than pT3+), whom some urologists feel are lower risk and may benefit from surgery alone, the SWOG study demonstrated a 2.5 year survival benefit with NAC.
- Additionally, surgical data demonstrates that we are not good at accurately determining T2 status – therefore, we can’t accurately identify the low-risk T2 patient that can forego chemotherapy
- MD Anderson data – 43% of low-risk T2 patients who underwent cystectomy without chemo were upstaged on final pathology
- Fox Chase data was even worse – 73% upstaged!
He lastly reviewed some of the same biomarkers that Dr. Black discussed. But, he pointed out that, while all had promising ability to predict benefit with NAC, there were still a significant number of patients who were negative for the test who benefitted from NAC – hence, these patients would lose out on good therapeutic options based on unrefined tests.
As such, these biomarkers are not yet ready for clinical use – they have no demonstrable impact on predicting outcome, treatment decision or monitoring therapy in MIBC. NAC should not be offered on the basis of these markers yet.
Go ahead and treat this patient with NAC and RC.
Presented by: HB Grossman, Houston, TX, USA
Discussants: P. Black Vancouver, Canada and J. Bellmunt Barcelona, Spain
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