title: Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy.
abstract: An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype.
  
  
  
  To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC.
  
  
  
  Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets).
  
  
  
  Gene expression analysis was used to assign subtypes.
  
  
  
  Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models.
  
  
  
  The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets.
  
  
  
  Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice.
  
  
  
  Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Seiler
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Hussam Al Deen
authors.initials: HAD
authors.lastname: Ashab
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Surgical Oncology, Division of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Bas W G
authors.initials: BWG
authors.lastname: van Rhijn
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Winters
authors.affiliation: Department of Urology, University Hospital of Southampton, Hampshire, UK.
authors.forename: James
authors.initials: J
authors.lastname: Douglas
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Van Kessel
authors.affiliation: Department of Surgical Oncology, Division of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Fransen van de Putte
authors.affiliation: Department of Urology, University Hospital of Southampton, Hampshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sommerlad
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Natalie Q
authors.initials: NQ
authors.lastname: Wang
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Voleak
authors.initials: V
authors.lastname: Choeurng
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Gibb
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Palmer-Aronsten
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Lucia L
authors.initials: LL
authors.lastname: Lam
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Buerki
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Division of Urological Research, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: Gottfrid
authors.initials: G
authors.lastname: Sjödahl
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Kardos
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Scott Department of Urologic Oncology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
authors.affiliation: Department of Medical Oncology, University Hospital of Southampton, Hampshire, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Crabb
authors.affiliation: Cross Cancer Institute, Department of Oncology, University of Alberta Edmonton, Alberta, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: North
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Joost L
authors.initials: JL
authors.lastname: Boormans
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wright
authors.affiliation: UC Davis Comprehensive Cancer Center, Sacramento, California, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Dall'Era
authors.affiliation: Department of Surgical Oncology, Division of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Michiel S
authors.initials: MS
authors.lastname: van der Heijden
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: pblack@mail.ubc.ca.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D059467:Transcriptome; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000073359:Exome Sequencing
chemical_list: D014408:Biomarkers, Tumor
keywords: Bladder cancer; Molecular subtypes; Neoadjuvant chemotherapy; Response prediction