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

Roland Seiler, Hussam Al Deen Ashab, Nicholas Erho, Bas W G van Rhijn, Brian Winters, James Douglas, Kim E. Van Kessel, Elisabeth E. Fransen van de Putte, Matthew Sommerlad, Natalie Q. Wang, Voleak Choeurng, Ewan A. Gibb, Beatrix Palmer-Aronsten, Lucia L. Lam, Christine Buerki, Elai Davicioni, Gottfrid Sjödahl, Jordan Kardos, Katherine A. Hoadley, Seth P. Lerner & 14 others David J. McConkey, Woonyoung Choi, William Y. Kim, Bernhard Kiss, George N. Thalmann, Tilman Todenhöfer, Simon J. Crabb, Scott North, Ellen C. Zwarthoff, Joost L. Boormans, Jonathan Wright, Marc Dall'Era, Michiel S. van der Heijden, Peter C. Black

Research output: Contribution to journalArticle

177 Citations (Scopus)

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. 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.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - 2017

Fingerprint

Urinary Bladder Neoplasms
Drug Therapy
Muscles
Survival
Neoplasms
Gene Expression
Neoplasm Genes
Gene Expression Profiling
Proportional Hazards Models
ROC Curve
Cisplatin
Retrospective Studies

Keywords

  • Bladder cancer
  • Molecular subtypes
  • Neoadjuvant chemotherapy
  • Response prediction

ASJC Scopus subject areas

  • Urology

Cite this

Seiler, R., Ashab, H. A. D., Erho, N., van Rhijn, B. W. G., Winters, B., Douglas, J., ... Black, P. C. (Accepted/In press). Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. European Urology. https://doi.org/10.1016/j.eururo.2017.03.030

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; Van Kessel, Kim E.; Fransen van de Putte, Elisabeth E.; Sommerlad, Matthew; Wang, Natalie Q.; Choeurng, Voleak; Gibb, Ewan A.; Palmer-Aronsten, Beatrix; Lam, Lucia L.; Buerki, Christine; Davicioni, Elai; Sjödahl, Gottfrid; Kardos, Jordan; Hoadley, Katherine A.; Lerner, Seth P.; McConkey, David J.; Choi, Woonyoung; Kim, William Y.; Kiss, Bernhard; Thalmann, George N.; Todenhöfer, Tilman; Crabb, Simon J.; North, Scott; Zwarthoff, Ellen C.; Boormans, Joost L.; Wright, Jonathan; Dall'Era, Marc; van der Heijden, Michiel S.; Black, Peter C.

In: European Urology, 2017.

Research output: Contribution to journalArticle

Seiler, R, Ashab, HAD, Erho, N, van Rhijn, BWG, Winters, B, Douglas, J, Van Kessel, KE, Fransen van de Putte, EE, Sommerlad, M, Wang, NQ, Choeurng, V, Gibb, EA, Palmer-Aronsten, B, Lam, LL, Buerki, C, Davicioni, E, Sjödahl, G, Kardos, J, Hoadley, KA, Lerner, SP, McConkey, DJ, Choi, W, Kim, WY, Kiss, B, Thalmann, GN, Todenhöfer, T, Crabb, SJ, North, S, Zwarthoff, EC, Boormans, JL, Wright, J, Dall'Era, M, van der Heijden, MS & Black, PC 2017, 'Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy', European Urology. https://doi.org/10.1016/j.eururo.2017.03.030
Seiler, Roland ; Ashab, Hussam Al Deen ; Erho, Nicholas ; van Rhijn, Bas W G ; Winters, Brian ; Douglas, James ; Van Kessel, Kim E. ; Fransen van de Putte, Elisabeth E. ; Sommerlad, Matthew ; Wang, Natalie Q. ; Choeurng, Voleak ; Gibb, Ewan A. ; Palmer-Aronsten, Beatrix ; Lam, Lucia L. ; Buerki, Christine ; Davicioni, Elai ; Sjödahl, Gottfrid ; Kardos, Jordan ; Hoadley, Katherine A. ; Lerner, Seth P. ; McConkey, David J. ; Choi, Woonyoung ; Kim, William Y. ; Kiss, Bernhard ; Thalmann, George N. ; Todenhöfer, Tilman ; Crabb, Simon J. ; North, Scott ; Zwarthoff, Ellen C. ; Boormans, Joost L. ; Wright, Jonathan ; Dall'Era, Marc ; van der Heijden, Michiel S. ; Black, Peter C. / Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. In: European Urology. 2017.
@article{0aa3a4aa64ab408aa3d24a99d0521d5c,
title = "Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy",
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. 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.",
keywords = "Bladder cancer, Molecular subtypes, Neoadjuvant chemotherapy, Response prediction",
author = "Roland Seiler and Ashab, {Hussam Al Deen} and Nicholas Erho and {van Rhijn}, {Bas W G} and Brian Winters and James Douglas and {Van Kessel}, {Kim E.} and {Fransen van de Putte}, {Elisabeth E.} and Matthew Sommerlad and Wang, {Natalie Q.} and Voleak Choeurng and Gibb, {Ewan A.} and Beatrix Palmer-Aronsten and Lam, {Lucia L.} and Christine Buerki and Elai Davicioni and Gottfrid Sj{\"o}dahl and Jordan Kardos and Hoadley, {Katherine A.} and Lerner, {Seth P.} and McConkey, {David J.} and Woonyoung Choi and Kim, {William Y.} and Bernhard Kiss and Thalmann, {George N.} and Tilman Todenh{\"o}fer and Crabb, {Simon J.} and Scott North and Zwarthoff, {Ellen C.} and Boormans, {Joost L.} and Jonathan Wright and Marc Dall'Era and {van der Heijden}, {Michiel S.} and Black, {Peter C.}",
year = "2017",
doi = "10.1016/j.eururo.2017.03.030",
language = "English (US)",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",

}

TY - JOUR

T1 - Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy

AU - Seiler, Roland

AU - Ashab, Hussam Al Deen

AU - Erho, Nicholas

AU - van Rhijn, Bas W G

AU - Winters, Brian

AU - Douglas, James

AU - Van Kessel, Kim E.

AU - Fransen van de Putte, Elisabeth E.

AU - Sommerlad, Matthew

AU - Wang, Natalie Q.

AU - Choeurng, Voleak

AU - Gibb, Ewan A.

AU - Palmer-Aronsten, Beatrix

AU - Lam, Lucia L.

AU - Buerki, Christine

AU - Davicioni, Elai

AU - Sjödahl, Gottfrid

AU - Kardos, Jordan

AU - Hoadley, Katherine A.

AU - Lerner, Seth P.

AU - McConkey, David J.

AU - Choi, Woonyoung

AU - Kim, William Y.

AU - Kiss, Bernhard

AU - Thalmann, George N.

AU - Todenhöfer, Tilman

AU - Crabb, Simon J.

AU - North, Scott

AU - Zwarthoff, Ellen C.

AU - Boormans, Joost L.

AU - Wright, Jonathan

AU - Dall'Era, Marc

AU - van der Heijden, Michiel S.

AU - Black, Peter C.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Bladder cancer

KW - Molecular subtypes

KW - Neoadjuvant chemotherapy

KW - Response prediction

UR - http://www.scopus.com/inward/record.url?scp=85017144247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017144247&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2017.03.030

DO - 10.1016/j.eururo.2017.03.030

M3 - Article

JO - European Urology

JF - European Urology

SN - 0302-2838

ER -