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, Vincenza (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Wetterskog, Daniel (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Sharabiani, M. T. A. (Royal Marsden NHS Foundation Trust. Research Data Management and Statistics Unit)
Grande, Enrique (Hospital Universitario Ramón y Cajal (Madrid))
Fernandez Perez, M. P. (Hospital General Universitario Morales Meseguer (Múrcia))
Jayaram, Anuradha (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Salvi, S. (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Castellano, Daniel (Hospital Universitario 12 de Octubre (Madrid))
Romanel, A. (Università di Trento. Centro di Biologia Integrata)
Lolli, C. (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Casadio, Valentina (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Gurioli, Giorgia (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Amadori, D. (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Font Guiteras, Antoni (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Vazquez Estevez, S. (Hospital Universitario Lucus Augusti (Lugo))
González-del-Alba, Aránzazu (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
Mellado, B. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Fernandez Calvo, O. (Complejo Hospitalario Universitario de Ourense)
Méndez Vidal, M. J. (Hospital Universitario Reina Sofía (Còrdova, Espanya))
Climent, Miguel Ángel (Fundació Institut Valencià d'Oncologia)
Durán, Ignacio (Instituto de Biomedicina de Sevilla)
Gallardo, Eduard (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Rodríguez Sánchez, Ángel (Hospital Universitario de León)
Santander, C. (Hospital Universitario Miguel Servet (Saragossa))
Sáez, M. I. (Hospital Regional Universitario de Málaga)
Puente, J. (Hospital Clínico San Carlos (Madrid))
Gasi Tandefelt, D. (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Wingate, Anna (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Dearnaley, David (Royal Marsden NHS Foundation Trust. Academic Urology Unit)
Demichelis, F. (Università di Trento. Centro di Biologia Integrata)
De Giorgi, Ugo (Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS)
Gonzalez-Billalabeitia, Enrique (Hospital General Universitario Morales Meseguer (Múrcia))
Attard, Gerhardt (Centre for Evolution and Cancer. The Institute of Cancer Research, London)
Spanish Oncology Genitourinary Group
Universitat Autònoma de Barcelona

Fecha:	2017
Resumen:	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-naïve and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve 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; P¼0. 03, and HR 1. 95; 95% CI 1. 23-3. 11; P¼0. 01, respectively) and rate of PSA decline50% [odds ratio (OR), 4. 7; 95% CI 1. 17-19. 17; P¼0. 035 and OR, 5. 0; 95% CI 1. 70-14. 91; P¼0. 003, respectively]. ARmutations [2105T>A (p. L702H) and 520 3_ $a 2632A>G (p. T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naı¨ve abiraterone-treated patients and were also associated with worse OS (HR 3. 26; 95% CI 1. 47-not reached; P¼0. 004). There was no interaction between AR and docetaxel status (P¼0. 83 for OS, P¼0. 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; P¼0. 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).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Castration-resistant prostate cancer ; Androgen receptor ; Plasma DNA ; Enzalutamide ; Abiraterone ; Biomarker
Publicado en:	Annals of oncology, Núm. 28 (2017) , p. 1508-1516, ISSN 1569-8041

9 p, 341.6 KB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Instituto de Investigación e Innovación Parc Taulí (I3PT)
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