Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study

Background: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemothera...

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Autores: Conteduca, V, Wetterskog, D, Sharabiani, MTA, Grande, E, Fernandez-Perez, MP, Jayaram, A, Salvi, S, Castellano, D, Romanel, A, Lolli, C, Casadio, V, Gurioli, G, Amadori, D, Font, A, Vazquez-Estevez, S, del Alba, AG, Mellado, B, Fernandez-Calvo, O, Méndez-Vidal, MJ, Climent, MA, Duran, I, Gallardo, E, Rodriguez, A, Santander, C, Sáez, MI, Puente, J, Tandefelt, DG, Wingate, A, Dearnaley, D, Demichelis, F, De Giorgi, U, Gonzalez-Billalabeitia, E, Attard, G
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p5366
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/5366
Access Level:acceso abierto
Palabra clave:castration-resistant prostate cancer
androgen receptor
plasma DNA
enzalutamide
abiraterone
biomarker
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repository_id_str
spelling Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker studyConteduca, VWetterskog, DSharabiani, MTAGrande, EFernandez-Perez, MPJayaram, ASalvi, SCastellano, DRomanel, ALolli, CCasadio, VGurioli, GAmadori, DFont, AVazquez-Estevez, Sdel Alba, AGMellado, BFernandez-Calvo, OMéndez-Vidal, MJCliment, MADuran, IGallardo, ERodriguez, ASantander, CSáez, MIPuente, JTandefelt, DGWingate, ADearnaley, DDemichelis, FDe Giorgi, UGonzalez-Billalabeitia, EAttard, Gcastration-resistant prostate cancerandrogen receptorplasma DNAenzalutamideabirateronebiomarkerBackground: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naive and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naive patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naive and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P<0.001 and HR 3.81; 95% CI 2.28-6.37; P<0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline >= 50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. ARmutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naive abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P<0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P<0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. Conclusion: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. Clinical Trial number: NCT02288936 (PREMIERE trial).ELSEVIER2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://i3pt.portalinvestigacion.com/publicaciones/5366ANNALS OF ONCOLOGYISSN: 09237534ISSNe: 15698041reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulíinstname:Institut d'Investigació i Innovació Parc Taulí (I3PT)Inglésinfo:eu-repo/semantics/openAccessoai:i3pt.fundanetsuite.com:p53662026-06-21T15:30:37Z
dc.title.none.fl_str_mv Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
title Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
spellingShingle Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
Conteduca, V
castration-resistant prostate cancer
androgen receptor
plasma DNA
enzalutamide
abiraterone
biomarker
title_short Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
title_full Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
title_fullStr Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
title_full_unstemmed Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
title_sort Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
dc.creator.none.fl_str_mv Conteduca, V
Wetterskog, D
Sharabiani, MTA
Grande, E
Fernandez-Perez, MP
Jayaram, A
Salvi, S
Castellano, D
Romanel, A
Lolli, C
Casadio, V
Gurioli, G
Amadori, D
Font, A
Vazquez-Estevez, S
del Alba, AG
Mellado, B
Fernandez-Calvo, O
Méndez-Vidal, MJ
Climent, MA
Duran, I
Gallardo, E
Rodriguez, A
Santander, C
Sáez, MI
Puente, J
Tandefelt, DG
Wingate, A
Dearnaley, D
Demichelis, F
De Giorgi, U
Gonzalez-Billalabeitia, E
Attard, G
author Conteduca, V
author_facet Conteduca, V
Wetterskog, D
Sharabiani, MTA
Grande, E
Fernandez-Perez, MP
Jayaram, A
Salvi, S
Castellano, D
Romanel, A
Lolli, C
Casadio, V
Gurioli, G
Amadori, D
Font, A
Vazquez-Estevez, S
del Alba, AG
Mellado, B
Fernandez-Calvo, O
Méndez-Vidal, MJ
Climent, MA
Duran, I
Gallardo, E
Rodriguez, A
Santander, C
Sáez, MI
Puente, J
Tandefelt, DG
Wingate, A
Dearnaley, D
Demichelis, F
De Giorgi, U
Gonzalez-Billalabeitia, E
Attard, G
author_role author
author2 Wetterskog, D
Sharabiani, MTA
Grande, E
Fernandez-Perez, MP
Jayaram, A
Salvi, S
Castellano, D
Romanel, A
Lolli, C
Casadio, V
Gurioli, G
Amadori, D
Font, A
Vazquez-Estevez, S
del Alba, AG
Mellado, B
Fernandez-Calvo, O
Méndez-Vidal, MJ
Climent, MA
Duran, I
Gallardo, E
Rodriguez, A
Santander, C
Sáez, MI
Puente, J
Tandefelt, DG
Wingate, A
Dearnaley, D
Demichelis, F
De Giorgi, U
Gonzalez-Billalabeitia, E
Attard, G
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv castration-resistant prostate cancer
androgen receptor
plasma DNA
enzalutamide
abiraterone
biomarker
topic castration-resistant prostate cancer
androgen receptor
plasma DNA
enzalutamide
abiraterone
biomarker
description Background: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naive and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naive patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naive and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P<0.001 and HR 3.81; 95% CI 2.28-6.37; P<0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline >= 50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. ARmutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naive abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P<0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P<0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. Conclusion: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. Clinical Trial number: NCT02288936 (PREMIERE trial).
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://i3pt.portalinvestigacion.com/publicaciones/5366
url https://i3pt.portalinvestigacion.com/publicaciones/5366
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER
publisher.none.fl_str_mv ELSEVIER
dc.source.none.fl_str_mv ANNALS OF ONCOLOGY
ISSN: 09237534
ISSNe: 15698041
reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
instname:Institut d'Investigació i Innovació Parc Taulí (I3PT)
instname_str Institut d'Investigació i Innovació Parc Taulí (I3PT)
reponame_str r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
collection r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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