Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes
Background: Metastatic prostate cancer (CaP) treatments are evolving rapidly but without evidence-based biomarkers to predict responses, and to maximize remissions and survival. Objective: To determine the activity of androgen receptor (AR), the target for default first-line systemic treatment, in l...
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Format: | Article |
Language: | English |
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Elsevier
2020-12-01
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Series: | European Urology Open Science |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S266616832035833X |
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doaj-ba587ec25e6b4c92b3f6ddb1ad16913f |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Salma Ben-Salem Qiang Hu Yang Liu Mohammed Alshalalfa Xin Zhao Irene Wang Varadha Balaji Venkadakrishnan Dhirodatta Senapati Sangeeta Kumari Deli Liu Andrea Sboner Christopher E. Barbieri Felix Feng Jean-Noel Billaud Elai Davicioni Song Liu Hannelore V. Heemers |
spellingShingle |
Salma Ben-Salem Qiang Hu Yang Liu Mohammed Alshalalfa Xin Zhao Irene Wang Varadha Balaji Venkadakrishnan Dhirodatta Senapati Sangeeta Kumari Deli Liu Andrea Sboner Christopher E. Barbieri Felix Feng Jean-Noel Billaud Elai Davicioni Song Liu Hannelore V. Heemers Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes European Urology Open Science Disease stratification Treatment response Hormonal therapy Chemotherapy Radiotherapy Biomarker |
author_facet |
Salma Ben-Salem Qiang Hu Yang Liu Mohammed Alshalalfa Xin Zhao Irene Wang Varadha Balaji Venkadakrishnan Dhirodatta Senapati Sangeeta Kumari Deli Liu Andrea Sboner Christopher E. Barbieri Felix Feng Jean-Noel Billaud Elai Davicioni Song Liu Hannelore V. Heemers |
author_sort |
Salma Ben-Salem |
title |
Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes |
title_short |
Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes |
title_full |
Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes |
title_fullStr |
Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes |
title_full_unstemmed |
Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes |
title_sort |
diversity in androgen receptor action among treatment-naïve prostate cancers is reflected in treatment response predictions and molecular subtypes |
publisher |
Elsevier |
series |
European Urology Open Science |
issn |
2666-1683 |
publishDate |
2020-12-01 |
description |
Background: Metastatic prostate cancer (CaP) treatments are evolving rapidly but without evidence-based biomarkers to predict responses, and to maximize remissions and survival. Objective: To determine the activity of androgen receptor (AR), the target for default first-line systemic treatment, in localized treatment-naïve CaP and its association with clinical risk factors, molecular markers, CaP subtypes, and predictors of treatment response. Design, setting, and participants: We examined 452 bona fide AR target genes in clinical-grade expression profiles from 6532 such CaPs collected between 2013 and 2017 by US physicians ordering the Decipher RP test. Results were validated in three independent smaller cohorts (n = 73, 90, and 127) and clinical CaP AR ChIP-Seq data. Association with CaP differentiation and progression was analyzed in independent datasets. Outcome measurements and statistical analysis: Unsupervised clustering of CaPs based on AR target gene expression was aligned with clinical variables, differentiation scores, molecular subtypes, and predictors of response to hormonal therapy, radiotherapy, and chemotherapy. AR target gene sets were analyzed via Gene Set Enrichment Analysis for differentiation and treatment resistance, Ingenuity Pathway Analysis for associated biology, and Cistrome for genomic AR binding site (ARBS) composition. Results and limitations: Expression of eight AR target gene subsignatures gave rise to five CaP clusters, which were preferentially associated with CaP molecular subtypes, differentiation, and predictors of treatment response rather than with clinical variables. Subsignatures differed in contribution to CaP progression, luminal/basal differentiation, CaP biology, and ARBS composition. Validation in prospective trials and optimized quantitation are needed for clinical implementation. Conclusions: Measurement of AR activity patterns in treatment-naïve CaP may serve as a first branch of an evidence-based decision tree to optimize personalized treatment plans. Patient summary: Treatment options for metastatic prostate cancer are increasing without information needed to choose the right treatment for the right patient. We found variation in the behavior of the target for the default first-line therapy before treatment, which may help optimize treatment plans. |
topic |
Disease stratification Treatment response Hormonal therapy Chemotherapy Radiotherapy Biomarker |
url |
http://www.sciencedirect.com/science/article/pii/S266616832035833X |
work_keys_str_mv |
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doaj-ba587ec25e6b4c92b3f6ddb1ad16913f2020-12-30T04:23:00ZengElsevierEuropean Urology Open Science2666-16832020-12-01223444Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular SubtypesSalma Ben-Salem0Qiang Hu1Yang Liu2Mohammed Alshalalfa3Xin Zhao4Irene Wang5Varadha Balaji Venkadakrishnan6Dhirodatta Senapati7Sangeeta Kumari8Deli Liu9Andrea Sboner10Christopher E. Barbieri11Felix Feng12Jean-Noel Billaud13Elai Davicioni14Song Liu15Hannelore V. Heemers16Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USADecipher Biosciences, San Diego, CA, USADecipher Biosciences, San Diego, CA, USA; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USADecipher Biosciences, San Diego, CA, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USADepartment of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA; Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USADepartment of Cancer Biology, Cleveland Clinic, Cleveland, OH, USADepartment of Cancer Biology, Cleveland Clinic, Cleveland, OH, USADepartment of Urology, Weill Cornell Medicine, New York, NY, USADepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USADepartment of Urology, Weill Cornell Medicine, New York, NY, USADepartment of Radiation Oncology, University of California San Francisco, San Francisco, CA, USAQiagen Digital Insights, Redwood City, CA, USADecipher Biosciences, San Diego, CA, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USADepartment of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA; Corresponding author. Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, NB-40, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel. +1-216-4457357.Background: Metastatic prostate cancer (CaP) treatments are evolving rapidly but without evidence-based biomarkers to predict responses, and to maximize remissions and survival. Objective: To determine the activity of androgen receptor (AR), the target for default first-line systemic treatment, in localized treatment-naïve CaP and its association with clinical risk factors, molecular markers, CaP subtypes, and predictors of treatment response. Design, setting, and participants: We examined 452 bona fide AR target genes in clinical-grade expression profiles from 6532 such CaPs collected between 2013 and 2017 by US physicians ordering the Decipher RP test. Results were validated in three independent smaller cohorts (n = 73, 90, and 127) and clinical CaP AR ChIP-Seq data. Association with CaP differentiation and progression was analyzed in independent datasets. Outcome measurements and statistical analysis: Unsupervised clustering of CaPs based on AR target gene expression was aligned with clinical variables, differentiation scores, molecular subtypes, and predictors of response to hormonal therapy, radiotherapy, and chemotherapy. AR target gene sets were analyzed via Gene Set Enrichment Analysis for differentiation and treatment resistance, Ingenuity Pathway Analysis for associated biology, and Cistrome for genomic AR binding site (ARBS) composition. Results and limitations: Expression of eight AR target gene subsignatures gave rise to five CaP clusters, which were preferentially associated with CaP molecular subtypes, differentiation, and predictors of treatment response rather than with clinical variables. Subsignatures differed in contribution to CaP progression, luminal/basal differentiation, CaP biology, and ARBS composition. Validation in prospective trials and optimized quantitation are needed for clinical implementation. Conclusions: Measurement of AR activity patterns in treatment-naïve CaP may serve as a first branch of an evidence-based decision tree to optimize personalized treatment plans. Patient summary: Treatment options for metastatic prostate cancer are increasing without information needed to choose the right treatment for the right patient. We found variation in the behavior of the target for the default first-line therapy before treatment, which may help optimize treatment plans.http://www.sciencedirect.com/science/article/pii/S266616832035833XDisease stratificationTreatment responseHormonal therapyChemotherapyRadiotherapyBiomarker |