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Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients

Holmsten, Karin ; Sjödahl, Gottfrid LU ; Abrahamsson, Johan LU ; Bernardo, Carina LU orcid ; Eriksson, Pontus LU ; Höglund, Mattias LU ; Liedberg, Fredrik LU and Ullén, Anders (2024) In JCO Precision Oncology 8.
Abstract

PURPOSE: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.

PATIENTS AND METHODS: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS).... (More)

PURPOSE: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.

PATIENTS AND METHODS: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.

RESULTS: Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.

CONCLUSION: This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Male, Cisplatin/therapeutic use, Female, Aged, Middle Aged, Retrospective Studies, Urologic Neoplasms/drug therapy, Antineoplastic Agents/therapeutic use, Aged, 80 and over, Adult, Urinary Bladder Neoplasms/drug therapy, Carcinoma, Transitional Cell/drug therapy
in
JCO Precision Oncology
volume
8
article number
e2400209
publisher
American Society of Clinical Oncology
external identifiers
  • scopus:85206927523
  • pmid:39348658
ISSN
2473-4284
DOI
10.1200/PO.24.00209
language
English
LU publication?
yes
id
4bce91ce-bc17-4431-b7b5-0d209cd16290
date added to LUP
2024-10-02 11:45:32
date last changed
2025-07-01 03:10:13
@article{4bce91ce-bc17-4431-b7b5-0d209cd16290,
  abstract     = {{<p>PURPOSE: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.</p><p>PATIENTS AND METHODS: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.</p><p>RESULTS: Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P &lt; .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.</p><p>CONCLUSION: This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.</p>}},
  author       = {{Holmsten, Karin and Sjödahl, Gottfrid and Abrahamsson, Johan and Bernardo, Carina and Eriksson, Pontus and Höglund, Mattias and Liedberg, Fredrik and Ullén, Anders}},
  issn         = {{2473-4284}},
  keywords     = {{Humans; Male; Cisplatin/therapeutic use; Female; Aged; Middle Aged; Retrospective Studies; Urologic Neoplasms/drug therapy; Antineoplastic Agents/therapeutic use; Aged, 80 and over; Adult; Urinary Bladder Neoplasms/drug therapy; Carcinoma, Transitional Cell/drug therapy}},
  language     = {{eng}},
  publisher    = {{American Society of Clinical Oncology}},
  series       = {{JCO Precision Oncology}},
  title        = {{Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients}},
  url          = {{http://dx.doi.org/10.1200/PO.24.00209}},
  doi          = {{10.1200/PO.24.00209}},
  volume       = {{8}},
  year         = {{2024}},
}