Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer
Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer
PURPOSE: After cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied.
EXPERIMENTAL DESIGN: RC 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 CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry 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 consensus clustering revealed four distinct consensus clusters (CC). 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 pre-treatment 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.
CONCLUSION: This study expands our knowledge on muscle-invasive bladder cancer 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.
Journal Article
Seiler, Roland
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Gibb, Ewan A.
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Wang, Natalie Q.
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Oo, Htoo Zarni
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Lam, Hung-Ming
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Van Kessel, Kim E.
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Voskuilen, Charlotte S.
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Winters, Brian
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Erho, Nicholas G.
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Takhar, Mandeep M.
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Douglas, James
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Vakar-Lopez, Funda
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Crabb, Simon J.
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van Rhijn, Bas W.G.
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Fransen van de Putte, Elisabeth E.
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Zwarthoff, Ellen C.
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Thalmann, George N.
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Davicioni, Elai
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Boormans, Joost L.
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Dall'Era, Marc
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van der Heijden, Michiel S.
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Wright, Jonathan L.
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Black, Peter C.
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Seiler, Roland
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Gibb, Ewan A.
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Wang, Natalie Q.
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Oo, Htoo Zarni
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Lam, Hung-Ming
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Van Kessel, Kim E.
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Voskuilen, Charlotte S.
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Winters, Brian
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Erho, Nicholas G.
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Takhar, Mandeep M.
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Douglas, James
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Vakar-Lopez, Funda
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Crabb, Simon J.
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van Rhijn, Bas W.G.
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Fransen van de Putte, Elisabeth E.
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Zwarthoff, Ellen C.
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Thalmann, George N.
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Davicioni, Elai
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Boormans, Joost L.
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Dall'Era, Marc
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van der Heijden, Michiel S.
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Wright, Jonathan L.
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Black, Peter C.
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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 G., 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. and Black, Peter C.
(2018)
Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Clinical Cancer Research.
(doi:10.1158/1078-0432.CCR-18-1106).
Abstract
PURPOSE: After cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied.
EXPERIMENTAL DESIGN: RC 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 CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry 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 consensus clustering revealed four distinct consensus clusters (CC). 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 pre-treatment 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.
CONCLUSION: This study expands our knowledge on muscle-invasive bladder cancer 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.
Text
Seiler divergent biological reponse to NAC
- Accepted Manuscript
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Accepted/In Press date: 11 September 2018
e-pub ahead of print date: 17 September 2018
Keywords:
Journal Article
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Local EPrints ID: 423818
URI: http://eprints.soton.ac.uk/id/eprint/423818
ISSN: 1078-0432
PURE UUID: e74700ad-609e-46b1-9495-40d7577d5f11
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Date deposited: 02 Oct 2018 16:30
Last modified: 16 Mar 2024 07:07
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Contributors
Author:
Roland Seiler
Author:
Ewan A. Gibb
Author:
Natalie Q. Wang
Author:
Htoo Zarni Oo
Author:
Hung-Ming Lam
Author:
Kim E. Van Kessel
Author:
Charlotte S. Voskuilen
Author:
Brian Winters
Author:
Nicholas G. Erho
Author:
Mandeep M. Takhar
Author:
James Douglas
Author:
Funda Vakar-Lopez
Author:
Bas W.G. van Rhijn
Author:
Elisabeth E. Fransen van de Putte
Author:
Ellen C. Zwarthoff
Author:
George N. Thalmann
Author:
Elai Davicioni
Author:
Joost L. Boormans
Author:
Marc Dall'Era
Author:
Michiel S. van der Heijden
Author:
Jonathan L. Wright
Author:
Peter C. Black
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