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Detecting predictive androgen receptor modifications in circulating prostate cancer cells

Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two...

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Autores principales: Steinestel, Julie, Luedeke, Manuel, Arndt, Annette, Schnoeller, Thomas J., Lennerz, Jochen K., Wurm, Carina, Maier, Christiane, Cronauer, Marcus V., Steinestel, Konrad, Schrader, Andres J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609250/
https://www.ncbi.nlm.nih.gov/pubmed/31289619
http://dx.doi.org/10.18632/oncotarget.3925
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author Steinestel, Julie
Luedeke, Manuel
Arndt, Annette
Schnoeller, Thomas J.
Lennerz, Jochen K.
Wurm, Carina
Maier, Christiane
Cronauer, Marcus V.
Steinestel, Konrad
Schrader, Andres J.
author_facet Steinestel, Julie
Luedeke, Manuel
Arndt, Annette
Schnoeller, Thomas J.
Lennerz, Jochen K.
Wurm, Carina
Maier, Christiane
Cronauer, Marcus V.
Steinestel, Konrad
Schrader, Andres J.
author_sort Steinestel, Julie
collection PubMed
description Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two most common AR modifications (AR-V7 splice variant and AR point mutations) in circulating tumor cells (CTCs). We devised a single-tube assay to detect AR-V7 splice variants and AR point mutations in CTCs using immunomagnetic cell isolation, followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 patients with PSA progression awaiting therapy switch. Comparison of response to newly administered therapy and CTC-AR-status allowed effect size estimation. Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Seventeen patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We estimated a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. Based on a conservative calculation, we estimated the effect size for molecularly-informed therapy switches for prospective clinical trial planning to ~27%. In summary, the ability to determine key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.
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spelling pubmed-66092502019-07-09 Detecting predictive androgen receptor modifications in circulating prostate cancer cells Steinestel, Julie Luedeke, Manuel Arndt, Annette Schnoeller, Thomas J. Lennerz, Jochen K. Wurm, Carina Maier, Christiane Cronauer, Marcus V. Steinestel, Konrad Schrader, Andres J. Oncotarget Research Paper Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two most common AR modifications (AR-V7 splice variant and AR point mutations) in circulating tumor cells (CTCs). We devised a single-tube assay to detect AR-V7 splice variants and AR point mutations in CTCs using immunomagnetic cell isolation, followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 patients with PSA progression awaiting therapy switch. Comparison of response to newly administered therapy and CTC-AR-status allowed effect size estimation. Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Seventeen patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We estimated a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. Based on a conservative calculation, we estimated the effect size for molecularly-informed therapy switches for prospective clinical trial planning to ~27%. In summary, the ability to determine key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment. Impact Journals LLC 2015-04-23 /pmc/articles/PMC6609250/ /pubmed/31289619 http://dx.doi.org/10.18632/oncotarget.3925 Text en Copyright: © 2019 Steinestel et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Steinestel, Julie
Luedeke, Manuel
Arndt, Annette
Schnoeller, Thomas J.
Lennerz, Jochen K.
Wurm, Carina
Maier, Christiane
Cronauer, Marcus V.
Steinestel, Konrad
Schrader, Andres J.
Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title_full Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title_fullStr Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title_full_unstemmed Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title_short Detecting predictive androgen receptor modifications in circulating prostate cancer cells
title_sort detecting predictive androgen receptor modifications in circulating prostate cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609250/
https://www.ncbi.nlm.nih.gov/pubmed/31289619
http://dx.doi.org/10.18632/oncotarget.3925
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