Identifier to cite or link to this item: http://hdl.handle.net/20.500.13003/9759
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
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ISSN: 0923-7534
eISSN: 1569-8041
WOS ID: 000404134100016
Scopus EID: 2-s2.0-85019315640
PMID: 28472366
Embase PUI: L619392989
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Conteduca, Vincenza; Wetterskog, D.; Sharabiani, M. T. A.; Grande, E.; Fernandez-Perez, M. P.; Jayaram, A.; Salvi, S.; Castellano, D.; Romanel, A.; Lolli, C.; Casadio, V.; Gurioli, G.; Amadori, D.; Font, Albert; Vazquez-Estevez, S.; Gonzalez Del Alba, Aranzazu; Mellado, B.; Fernandez-Calvo, O.; Mendez-Vidal, M. J.; Climent, M. A.; Duran, Ignacio; Gallardo, E.; Rodriguez, A.; Santander, C.; Saez, M. I.; Puente, J.; Tandefelt, D. Gasi; Wingate, A.; Dearnaley, D.; Demichelis, F.; De Giorgi, Ugo; Gonzalez-Billalabeitia, E.; Attard, G.; PREMIERE Collaborators; Spanish Oncology Genitourinary GrpPublication date
2017-07Document type
research articleCitation
Conteduca V, Wetterskog D, Sharabiani MTA, Grande E, Fernandez-Perez MP, Jayaram A, et al. 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. Ann Oncol. 2017 Jul;28(7):1508-16.Abstract
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).
Publisher version
https://dx.doi.org/10.1093/annonc/mdx155Keywords
castration-resistant prostate cancerandrogen receptor
plasma DNA
enzalutamide
abiraterone
biomarker
MeSH
Disease-Free SurvivalAged, 80 and over
Disease Progression
Aged
Adult
Humans
Multiplex Polymerase Chain Reaction
DNA Mutational Analysis
Male
Multivariate Analysis
Predictive Value of Tests
Time Factors
Europe
Biomarkers, Tumor
Phenylthiohydantoin
Risk Factors
Kaplan-Meier Estimate
Androstenes
Middle Aged
Circulating Tumor DNA
Prostatic Neoplasms, Castration-Resistant
Prospective Studies
Mutation
Receptors, Androgen
Precision Medicine
Proportional Hazards Models
Treatment Outcome
Antineoplastic Agents, Hormonal
Odds Ratio
Patient Selection
DeCS
Antineoplásicos HormonalesSelección de Paciente
Modelos de Riesgos Proporcionales
Resultado del Tratamiento
Oportunidad Relativa
Europa (Continente)
Análisis Mutacional de ADN
Masculino
Receptores Androgénicos
Persona de Mediana Edad
Estudios Prospectivos
Estimación de Kaplan-Meier
Progresión de la Enfermedad
Medicina de Precisión
Androstenos
Supervivencia sin Enfermedad
Factores de Tiempo
Análisis Multivariante
Neoplasias de la Próstata Resistentes a la Castración
Reacción en Cadena de la Polimerasa Multiplex
Biomarcadores de Tumor
Mutación
Feniltiohidantoína
Factores de Riesgo
Humanos
Valor Predictivo de las Pruebas
Anciano
Anciano de 80 o más Años
Adulto
ADN Tumoral Circulante
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Hospital Universitario Son Espases - HUSE > Comunicación científicaInstituto de Investigación Sanitaria Islas Baleares - IDISBA > Comunicación científica