Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

Roland Seiler, Ewan A. Gibb, Natalie Q. Wang, Htoo Zarni Oo, Hung Ming Lam, Kim E. van Kessel, Charlotte S. Voskuilen, Brian Winters, Nicholas Erho, Mandeep M. Takhar, James Douglas, Funda Vakar-Lopez, Simon J. Crabb, Bas W.G. van Rhijn, Elisabeth E. Fransen van de Putte, Ellen C. Zwarthoff, George N. Thalmann, Elai Davicioni, Joost L. Boormans, Marc Dall'EraMichiel S. van der Heijden, Jonathan L. Wright, Peter C. Black

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis. Conclusions: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

Original languageEnglish (US)
Pages (from-to)5082-5093
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

Fingerprint

Urinary Bladder Neoplasms
Cisplatin
Drug Therapy
Muscles
Cystectomy
Cluster Analysis
Neoplasms
Gene Expression
Molecular Models
Hematoxylin
Eosine Yellowish-(YS)
Wound Healing
Genes
Cicatrix
Research Design
Clinical Trials
T-Lymphocytes
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Seiler, R., Gibb, E. A., Wang, N. Q., Oo, H. Z., Lam, H. M., van Kessel, K. E., ... Black, P. C. (2019). Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Clinical Cancer Research, 25(16), 5082-5093. https://doi.org/10.1158/1078-0432.CCR-18-1106

Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. / Seiler, Roland; Gibb, Ewan A.; Wang, Natalie Q.; Oo, Htoo Zarni; Lam, Hung Ming; van Kessel, Kim E.; Voskuilen, Charlotte S.; Winters, Brian; Erho, Nicholas; Takhar, Mandeep M.; Douglas, James; Vakar-Lopez, Funda; Crabb, Simon J.; van Rhijn, Bas W.G.; Fransen van de Putte, Elisabeth E.; Zwarthoff, Ellen C.; Thalmann, George N.; Davicioni, Elai; Boormans, Joost L.; Dall'Era, Marc; van der Heijden, Michiel S.; Wright, Jonathan L.; Black, Peter C.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 5082-5093.

Research output: Contribution to journalArticle

Seiler, R, Gibb, EA, Wang, NQ, Oo, HZ, Lam, HM, van Kessel, KE, Voskuilen, CS, Winters, B, Erho, N, Takhar, MM, Douglas, J, Vakar-Lopez, F, Crabb, SJ, van Rhijn, BWG, Fransen van de Putte, EE, Zwarthoff, EC, Thalmann, GN, Davicioni, E, Boormans, JL, Dall'Era, M, van der Heijden, MS, Wright, JL & Black, PC 2019, 'Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer', Clinical Cancer Research, vol. 25, no. 16, pp. 5082-5093. https://doi.org/10.1158/1078-0432.CCR-18-1106
Seiler, Roland ; Gibb, Ewan A. ; Wang, Natalie Q. ; Oo, Htoo Zarni ; Lam, Hung Ming ; van Kessel, Kim E. ; Voskuilen, Charlotte S. ; Winters, Brian ; Erho, Nicholas ; Takhar, Mandeep M. ; Douglas, James ; Vakar-Lopez, Funda ; Crabb, Simon J. ; van Rhijn, Bas W.G. ; Fransen van de Putte, Elisabeth E. ; Zwarthoff, Ellen C. ; Thalmann, George N. ; Davicioni, Elai ; Boormans, Joost L. ; Dall'Era, Marc ; van der Heijden, Michiel S. ; Wright, Jonathan L. ; Black, Peter C. / Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 5082-5093.
@article{ecf631f45e7d483da14154507442257c,
title = "Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer",
abstract = "Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC), 60{\%} of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis. Conclusions: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.",
author = "Roland Seiler and Gibb, {Ewan A.} and Wang, {Natalie Q.} and Oo, {Htoo Zarni} and Lam, {Hung Ming} and {van Kessel}, {Kim E.} and Voskuilen, {Charlotte S.} and Brian Winters and Nicholas Erho and Takhar, {Mandeep M.} and James Douglas and Funda Vakar-Lopez and Crabb, {Simon J.} and {van Rhijn}, {Bas W.G.} and {Fransen van de Putte}, {Elisabeth E.} and Zwarthoff, {Ellen C.} and Thalmann, {George N.} and Elai Davicioni and Boormans, {Joost L.} and Marc Dall'Era and {van der Heijden}, {Michiel S.} and Wright, {Jonathan L.} and Black, {Peter C.}",
year = "2019",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-18-1106",
language = "English (US)",
volume = "25",
pages = "5082--5093",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

AU - Seiler, Roland

AU - Gibb, Ewan A.

AU - Wang, Natalie Q.

AU - Oo, Htoo Zarni

AU - Lam, Hung Ming

AU - van Kessel, Kim E.

AU - Voskuilen, Charlotte S.

AU - Winters, Brian

AU - Erho, Nicholas

AU - Takhar, Mandeep M.

AU - Douglas, James

AU - Vakar-Lopez, Funda

AU - Crabb, Simon J.

AU - van Rhijn, Bas W.G.

AU - Fransen van de Putte, Elisabeth E.

AU - Zwarthoff, Ellen C.

AU - Thalmann, George N.

AU - Davicioni, Elai

AU - Boormans, Joost L.

AU - Dall'Era, Marc

AU - van der Heijden, Michiel S.

AU - Wright, Jonathan L.

AU - Black, Peter C.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis. Conclusions: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

AB - Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis. Conclusions: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=85065572427&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065572427&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1106

DO - 10.1158/1078-0432.CCR-18-1106

M3 - Article

C2 - 30224344

AN - SCOPUS:85065572427

VL - 25

SP - 5082

EP - 5093

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 16

ER -