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Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy

Seiler, Roland; Ashab, Hussam Al Deen; Erho, Nicholas; van Rhijn, Bas W G; Winters, Brian; Douglas, James J; van Kessel, Kim E M; Fransen van de Putte, Elisabeth E.; Sommerlad, Matthew and Wang, Natalie Q., et al. (2017) In European Urology 72(4). p.544-554
Abstract

Background: 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. Objective: To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. Design, setting, and participants: 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.... (More)

Background: 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. Objective: To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. Design, setting, and participants: 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). Intervention: Gene expression analysis was used to assign subtypes. Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: 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. Patient summary: 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. Molecular subtypes in muscle-invasive bladder cancer appear have an impact on patient response to neoadjuvant chemotherapy (NAC); namely, patients with basal tumors showed the most benefit from NAC and should be prioritized for NAC. Moreover, these subtypes can be identified in a single sample by our discovered classifier.

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published
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keywords
Bladder cancer, Molecular subtypes, Neoadjuvant chemotherapy, Response prediction
in
European Urology
volume
72
issue
4
pages
544 - 554
publisher
Elsevier
external identifiers
  • scopus:85017144247
ISSN
0302-2838
DOI
10.1016/j.eururo.2017.03.030
language
English
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yes
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943368a1-3e60-4232-8f4f-c719e983c28e
date added to LUP
2017-05-15 16:23:04
date last changed
2017-09-20 12:50:34
@article{943368a1-3e60-4232-8f4f-c719e983c28e,
  abstract     = {<p>Background: 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. Objective: To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. Design, setting, and participants: 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). Intervention: Gene expression analysis was used to assign subtypes. Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: 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. Patient summary: 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. Molecular subtypes in muscle-invasive bladder cancer appear have an impact on patient response to neoadjuvant chemotherapy (NAC); namely, patients with basal tumors showed the most benefit from NAC and should be prioritized for NAC. Moreover, these subtypes can be identified in a single sample by our discovered classifier.</p>},
  author       = {Seiler, Roland and Ashab, Hussam Al Deen and Erho, Nicholas and van Rhijn, Bas W G and Winters, Brian and Douglas, James J and van Kessel, Kim E M and Fransen van de Putte, Elisabeth E. and Sommerlad, Matthew and Wang, Natalie Q. and Choeurng, Voleak and Gibb, Ewan A. and Palmer-Aronsten, Beatrix and Lam, Lucia L. and Buerki, Christine and Davicioni, Elai and Sjödahl, Gottfrid and Kardos, Jordan and Hoadley, Katherine A. and Lerner, Seth P. and McConkey, David J. and Choi, Woonyoung and Kim, William Y. and Kiss, Bernhard and Thalmann, George N. and Todenhöfer, Tilman and Crabb, Simon J. and North, Scott and Zwarthoff, Ellen C. and Boormans, Joost L. and Wright, Jonathan and Dall'Era, Marc and van der Heijden, Michiel S. and Black, Peter C.},
  issn         = {0302-2838},
  keyword      = {Bladder cancer,Molecular subtypes,Neoadjuvant chemotherapy,Response prediction},
  language     = {eng},
  number       = {4},
  pages        = {544--554},
  publisher    = {Elsevier},
  series       = {European Urology},
  title        = {Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy},
  url          = {http://dx.doi.org/10.1016/j.eururo.2017.03.030},
  volume       = {72},
  year         = {2017},
}