Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

William S. Chen, Rahul Aggarwal, Li Zhang, Shuang G. Zhao, George Thomas, Tomasz (Tom) Beer, David A. Quigley, Adam Foye, Denise Playdle, Jiaoti Huang, Paul Lloyd, Eric Lu, Duanchen Sun, Xiangnan Guan, Matthew Rettig, Martin Gleave, Christopher P. Evans, Jack Youngren, Lawrence True, Primo Lara & 8 others Vishal Kothari, Zheng Xia, Kim N. Chi, Robert E. Reiter, Christopher A. Maher, Felix Y. Feng, Eric J. Small, Joshi Alumkal

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated. Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance. Design, setting, and participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients. Outcome measurements and statistical analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test. Results and limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0 mo; p = 0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p = 0.01) and independently predictive of poor OS (median 13.6 vs 41.7 mo; p = 0.025). Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort. Patient summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Castration
Prostatic Neoplasms
Catenins
Survival Analysis
Survival
RNA Sequence Analysis
Mutation
Wnt Signaling Pathway
Genome
Genes
MDV 3100
DNA
Transcriptome
Neoplasm Metastasis
Biopsy

Keywords

  • Advanced prostate cancer
  • Castration-resistant
  • Clinical outcomes
  • Enzalutamide
  • Genomics
  • Metastatic prostate cancer
  • Prognostic factors

ASJC Scopus subject areas

  • Urology

Cite this

Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer. / Chen, William S.; Aggarwal, Rahul; Zhang, Li; Zhao, Shuang G.; Thomas, George; Beer, Tomasz (Tom); Quigley, David A.; Foye, Adam; Playdle, Denise; Huang, Jiaoti; Lloyd, Paul; Lu, Eric; Sun, Duanchen; Guan, Xiangnan; Rettig, Matthew; Gleave, Martin; Evans, Christopher P.; Youngren, Jack; True, Lawrence; Lara, Primo; Kothari, Vishal; Xia, Zheng; Chi, Kim N.; Reiter, Robert E.; Maher, Christopher A.; Feng, Felix Y.; Small, Eric J.; Alumkal, Joshi.

In: European Urology, 01.01.2019.

Research output: Contribution to journalArticle

Chen, WS, Aggarwal, R, Zhang, L, Zhao, SG, Thomas, G, Beer, TT, Quigley, DA, Foye, A, Playdle, D, Huang, J, Lloyd, P, Lu, E, Sun, D, Guan, X, Rettig, M, Gleave, M, Evans, CP, Youngren, J, True, L, Lara, P, Kothari, V, Xia, Z, Chi, KN, Reiter, RE, Maher, CA, Feng, FY, Small, EJ & Alumkal, J 2019, 'Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer', European Urology. https://doi.org/10.1016/j.eururo.2019.03.020
Chen, William S. ; Aggarwal, Rahul ; Zhang, Li ; Zhao, Shuang G. ; Thomas, George ; Beer, Tomasz (Tom) ; Quigley, David A. ; Foye, Adam ; Playdle, Denise ; Huang, Jiaoti ; Lloyd, Paul ; Lu, Eric ; Sun, Duanchen ; Guan, Xiangnan ; Rettig, Matthew ; Gleave, Martin ; Evans, Christopher P. ; Youngren, Jack ; True, Lawrence ; Lara, Primo ; Kothari, Vishal ; Xia, Zheng ; Chi, Kim N. ; Reiter, Robert E. ; Maher, Christopher A. ; Feng, Felix Y. ; Small, Eric J. ; Alumkal, Joshi. / Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer. In: European Urology. 2019.
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title = "Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer",
abstract = "Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated. Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance. Design, setting, and participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients. Outcome measurements and statistical analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test. Results and limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0 mo; p = 0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p = 0.01) and independently predictive of poor OS (median 13.6 vs 41.7 mo; p = 0.025). Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort. Patient summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.",
keywords = "Advanced prostate cancer, Castration-resistant, Clinical outcomes, Enzalutamide, Genomics, Metastatic prostate cancer, Prognostic factors",
author = "Chen, {William S.} and Rahul Aggarwal and Li Zhang and Zhao, {Shuang G.} and George Thomas and Beer, {Tomasz (Tom)} and Quigley, {David A.} and Adam Foye and Denise Playdle and Jiaoti Huang and Paul Lloyd and Eric Lu and Duanchen Sun and Xiangnan Guan and Matthew Rettig and Martin Gleave and Evans, {Christopher P.} and Jack Youngren and Lawrence True and Primo Lara and Vishal Kothari and Zheng Xia and Chi, {Kim N.} and Reiter, {Robert E.} and Maher, {Christopher A.} and Feng, {Felix Y.} and Small, {Eric J.} and Joshi Alumkal",
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day = "1",
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language = "English (US)",
journal = "European Urology",
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TY - JOUR

T1 - Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

AU - Chen, William S.

AU - Aggarwal, Rahul

AU - Zhang, Li

AU - Zhao, Shuang G.

AU - Thomas, George

AU - Beer, Tomasz (Tom)

AU - Quigley, David A.

AU - Foye, Adam

AU - Playdle, Denise

AU - Huang, Jiaoti

AU - Lloyd, Paul

AU - Lu, Eric

AU - Sun, Duanchen

AU - Guan, Xiangnan

AU - Rettig, Matthew

AU - Gleave, Martin

AU - Evans, Christopher P.

AU - Youngren, Jack

AU - True, Lawrence

AU - Lara, Primo

AU - Kothari, Vishal

AU - Xia, Zheng

AU - Chi, Kim N.

AU - Reiter, Robert E.

AU - Maher, Christopher A.

AU - Feng, Felix Y.

AU - Small, Eric J.

AU - Alumkal, Joshi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated. Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance. Design, setting, and participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients. Outcome measurements and statistical analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test. Results and limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0 mo; p = 0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p = 0.01) and independently predictive of poor OS (median 13.6 vs 41.7 mo; p = 0.025). Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort. Patient summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

AB - Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated. Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance. Design, setting, and participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients. Outcome measurements and statistical analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test. Results and limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0 mo; p = 0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p = 0.01) and independently predictive of poor OS (median 13.6 vs 41.7 mo; p = 0.025). Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort. Patient summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

KW - Advanced prostate cancer

KW - Castration-resistant

KW - Clinical outcomes

KW - Enzalutamide

KW - Genomics

KW - Metastatic prostate cancer

KW - Prognostic factors

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