Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

Gottfrid Sjödahl; Johan Abrahamsson; Karin Holmsten; Carina Bernardo; Gunilla Chebil; Pontus Eriksson; Iva Johansson; Petter Kollberg; Claes Lindh; Kristina Lövgren; Nour al Dain Marzouka; Hans Olsson; Mattias Höglund; Anders Ullén; Fredrik Liedberg

doi:10.1016/j.eururo.2021.10.035

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

Gottfrid Sjödahl, Johan Abrahamsson, Karin Holmsten, Carina Bernardo, Gunilla Chebil, Pontus Eriksson, Iva Johansson, Petter Kollberg, Claes Lindh, Kristina Lövgren, Nour al Dain Marzouka, Hans Olsson, Mattias Höglund, Anders Ullén, Fredrik Liedberg

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.

OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.

RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.

CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Original language	English
Pages (from-to)	523-532
Journal	European Urology
Volume	81
Issue number	5
Early online date	2021 Nov 12
DOIs	https://doi.org/10.1016/j.eururo.2021.10.035
Publication status	Published - 2022

Subject classification (UKÄ)

Urology and Nephrology
Cancer and Oncology

Free keywords

Basal/squamous
Bladder cancer
Chemotherapy
Cisplatin
Luminal
Molecular subtypes
Neoadjuvant
Osteopontin
Response
Signature
SPP1
Survival
Urothelial carcinoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.eururo.2021.10.035Licence: CC BY

1 Doctoral Thesis (compilation)

Advanced Bladder Cancer. Aspects of Diagnosis and Treatment.
Abrahamsson, J., 2021, Lund: Lund University, Faculty of Medicine. 59 p.
Research output: Thesis › Doctoral Thesis (compilation)

Cite this

Sjödahl, G., Abrahamsson, J., Holmsten, K., Bernardo, C., Chebil, G., Eriksson, P., Johansson, I., Kollberg, P., Lindh, C., Lövgren, K., Marzouka, N. A. D., Olsson, H., Höglund, M., Ullén, A., & Liedberg, F. (2022). Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes. European Urology, 81(5), 523-532. https://doi.org/10.1016/j.eururo.2021.10.035

@article{aebdccb8961a473db2cc8460073eff72,

title = "Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes",

abstract = "BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.",

keywords = "Basal/squamous, Bladder cancer, Chemotherapy, Cisplatin, Luminal, Molecular subtypes, Neoadjuvant, Osteopontin, Response, Signature, SPP1, Survival, Urothelial carcinoma",

author = "Gottfrid Sj{\"o}dahl and Johan Abrahamsson and Karin Holmsten and Carina Bernardo and Gunilla Chebil and Pontus Eriksson and Iva Johansson and Petter Kollberg and Claes Lindh and Kristina L{\"o}vgren and Marzouka, {Nour al Dain} and Hans Olsson and Mattias H{\"o}glund and Anders Ull{\'e}n and Fredrik Liedberg",

year = "2022",

doi = "10.1016/j.eururo.2021.10.035",

language = "English",

volume = "81",

pages = "523--532",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

}

Sjödahl, G , Abrahamsson, J, Holmsten, K, Bernardo, C, Chebil, G, Eriksson, P, Johansson, I, Kollberg, P, Lindh, C, Lövgren, K, Marzouka, NAD, Olsson, H, Höglund, M, Ullén, A & Liedberg, F 2022, 'Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes', European Urology, vol. 81, no. 5, pp. 523-532. https://doi.org/10.1016/j.eururo.2021.10.035

TY - JOUR

T1 - Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

AU - Sjödahl, Gottfrid

AU - Abrahamsson, Johan

AU - Holmsten, Karin

AU - Bernardo, Carina

AU - Chebil, Gunilla

AU - Eriksson, Pontus

AU - Johansson, Iva

AU - Kollberg, Petter

AU - Lindh, Claes

AU - Lövgren, Kristina

AU - Marzouka, Nour al Dain

AU - Olsson, Hans

AU - Höglund, Mattias

AU - Ullén, Anders

AU - Liedberg, Fredrik

PY - 2022

Y1 - 2022

N2 - BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

AB - BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

KW - Basal/squamous

KW - Bladder cancer

KW - Chemotherapy

KW - Cisplatin

KW - Luminal

KW - Molecular subtypes

KW - Neoadjuvant

KW - Osteopontin

KW - Response

KW - Signature

KW - SPP1

KW - Survival

KW - Urothelial carcinoma

U2 - 10.1016/j.eururo.2021.10.035

DO - 10.1016/j.eururo.2021.10.035

M3 - Article

C2 - 34782206

AN - SCOPUS:85119072622

SN - 0302-2838

VL - 81

SP - 523

EP - 532

JO - European Urology

JF - European Urology

IS - 5

ER -

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

Abstract

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Research output

Advanced Bladder Cancer. Aspects of Diagnosis and Treatment.

Cite this