ASCO GU 2020: Risk Stratification and Management of High-Risk Muscle Invasive Urothelial Carcinoma: Subtyping

San Francisco, California (UroToday.com) As part of the risk stratification and management of high-risk MIBC, William Kim, MD, discussed the important role of subtyping these patients. Over the past several years, Dr. Kim notes that there has bene a multitude of molecular subtypes of high-grade MIBC. A recent publication highlighted a consensus molecular classification of MIBC in order to achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.1 For this study, the panel used 1,750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. The panel identified a consensus set of six molecular classes: luminal papillary (24%), luminal non-specified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. Additionally, they provided a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. 

When regarding subtypes as prognostic biomarkers, basal subtype has consistently been correlated with a poor prognosis across several studies. Alternatively, luminal “papillary” tumors have a better prognosis than basal subtype. Without neoadjuvant chemotherapy, luminal and basal subtypes have good and bad prognosis, respectively. In two separate studies,2-3 basal subtype appears to be associated with improved survival after neoadjuvant chemotherapy. Furthermore, downstaging after neoadjuvant chemotherapy is associated with improved overall survival in all subtypes except basal subtype.2 As Dr. Kim notes, this has been referred to as the “basal bladder cancer paradox” in that basal tumors are not downstaged by neoadjuvant chemotherapy, but have improved survival. What we know is that downstaging to pT0 is well documented to correlate with improved OS. What we think we know is that neoadjuvant chemotherapy for basal urothelial carcinoma appears to prolong survival but does not necessarily result in downstaging of the tumor. Furthermore, we think that basal subtyping may be associated with improved survival after neoadjuvant chemotherapy regardless of downstaging. 

 

There are several explanations for this paradox, according to Dr. Kim:

  • The current results may not validate in prospective assessment
  • Basal bladder tumors actually have higher clinical stage than appreciated (ie. they actually do have higher downstaging rate)
  • Basal tumors may have dichotomy in response of primary versus metastatic sites in that the primary is chemo-refractory and the metastatic sites are chemosensitive

The molecular subtypes have been assessed in response to trimodal therapy (TMT), but to date there has been no clear subtype that has predicted response to TMT. According to Dr. Kim, further exploration with other classifiers is warranted for assessing subtypes in the domain of TMT. Furthermore, the correlation of subtyping to immunotherapy response in the metastatic setting remains conflicting. Currently there are two studies with three answers:
Subtyping_Studies.png

Dr. Kim concluded his talk on subtyping for MIBC with several take-home messages:

  • Molecular subtypes are prognostic
  • The clinical utility of subtypes as a predictive biomarker for neoadjuvant chemotherapy response suggests basal tumors may benefit the most from neoadjuvant chemotherapy but these findings require prospective validation

Presented by: William Y. Kim, MD, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md  at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California 

References:

  1. Kamoun A, de Reynies A, Allory Y, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol 2019 Sep 26 [Epub ahead of print]. 
  2. Seiler R, Ashab HAD, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol 2017 Oct;72(4):544-554.
  3. McConkey DJ, Choi W, Shen Y, et al. A prognostic gene expression signature in the molecular classification of chemotherapy-naïve urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: A Phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer. Eur Urol 2016 May;69(5):855-862. 
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