He began by highlighting that subtyping of bladder cancer dates back to 2003. Since that time, many groups have proposed many different approaches to subtyping. It wasn’t until 2014 that correlation with clinical outcomes was demonstrated.
He highlighted that molecular subtyping divides bladder cancer into basal and luminal subtypes. Each subtyping scheme then subsequently subdivides these two main strata. Dr. Black highlighted, that to make this approach both clinically and from a research perspective useful would require three things: first, a consensus classifier; second, a single patient classifier (which has been achieved); and third, a demonstration of utility.
Addressing each of these in turn, he first highlighted a recent publication from Dr. Kamoun and colleagues in European Urology which described a consensus molecular classification of muscle-invasive bladder cancer.1 This approach described 6 consensus subtypes as follows:
He highlighted that patients with luminal papillary tumors represent nearly a quarter of all patients and have the best survival while basal/squamous tumors represent nearly a third and have a relatively poor prognosis but may derive the greatest benefit from neoadjuvant chemotherapy.
Considering the utility of molecular subtyping, Dr. Black considered a number of contexts in which this may be assessed: risk stratification, to guide treatment, and as a framework for translational research. Focusing on the second of these, he first highlighted data from MD Anderson which, in 2014 demonstrated a differential response to neoadjuvant chemotherapy, based on their three strata model.2
Validation of this approach using a four-level classifier demonstrated that, among those who did not receive neoadjuvant chemotherapy, better outcomes were observed among those with luminal tumors. While this remained true among those receiving neoadjuvant chemotherapy, those with basal tumors also did well in this cohort, demonstrating a particular benefit to neoadjuvant chemotherapy in this group.
Dr. Black then highlighted that molecular subtyping is not the only potentially predictive biomarker, with alternatives including the COXEN model (based on RNA expression) and DNA damage repair gene mutations.
He proposed a sample trial design to assess the utility of a molecular sub-classification, as suggested by Dr. Meeks:
Dr. Black then considered the role of molecular subtyping among patients who receive trimodal therapy, rather than radical cystectomy. He highlighted data from Dr. Efstathiou which would suggest that bladder cancer-specific survival doesn’t differ based on molecular subtypes for patients who receive trimodal therapy. However, an RNA-based immune-infiltration signature did predict disease-specific survival among patients receiving trimodal therapy, but worse survival after neoadjuvant chemotherapy and radical cystectomy. This implies that molecular subtyping may provide treatment recommendations.
Based on recently published data from the PURE-01 trial, Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma, (PURE-01), Dr. Black highlighted that molecular subtyping could predict treatment outcomes, though the subgroups that did well differed compared to the cohort treated with neoadjuvant chemotherapy.
In summary, Dr. Black suggested that molecular subtyping may help us both understand underlying disease biology and direct patient-level treatment decision.
Presented by: Peter Black, MD, FACS, FRCSC, Khosrowshahi Family Chair, Senior Research Scientist, Vancouver Prostate Centre, Professor, Department of Urologic Sciences, University of British Columbia, Vancouver Prostate Center
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC) (#EMUC20 ), November 13th - 14th, 2020
- A Kamoun, A de Reyniès, Y Allory et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020 Apr;77(4):420-433.
- Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152-65