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Ann Oncol. 2017 Jul 1;28(7):1508-1516. doi: 10.1093/annonc/mdx155.

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.

Author information

1
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
2
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
3
Research Data Management and Statistics Unit, The Royal Marsden NHS Foundation Trust, London, UK.
4
Department of Medical Oncology, Hospital Ramón y Cajal, Madrid.
5
Department of Hematology & Medical Oncology, Hospital Universitario Morales Meseguer, IMIB-Universidad de Murcia, Murcia.
6
Academic Urology Unit, The Royal Marsden NHS Foundation Trust, London, UK.
7
Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
8
Centre for Integrative Biology, University of Trento, Trento, Italy.
9
Oncology Unit, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Badalona.
10
Department of Medical Oncology, H. Universitario Lucus Augusti, Lugo.
11
Department of Medical Oncology, H.U. Son Espases Mallorca, Mallorca.
12
Department of Medical Oncology, IDIBAPS Hospital Clinic, Barcelona.
13
Department of Medical Oncology, Hospital de Orense, Orense.
14
Department of Medical Oncology, Hospital Universitario Reina Sofía, Córdoba.
15
Department of Medical Oncology, Instituto Valenciano de Oncología Valencia, Valencia.
16
Department of Medical Oncology, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla.
17
Department of Medical Oncology, H.U. Parc Taulí, Sabadell, Barcelona.
18
Department of Medical Oncology, Hospital de León, León.
19
Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza.
20
Department of Medical Oncology, Hospital Regional y Hospital Virgen de la Victoria, Malaga.
21
Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain.
22
Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
23
Institute for Precision Medicine, Weill Cornell Medicine, New York, USA.
24
Department of Medical Oncology, Universidad Católica San Antonio de Murcia-UCAM, Murcia, Spain.

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-naïve and 98 post-docetaxel 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; 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]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve 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).

KEYWORDS:

abiraterone; androgen receptor; biomarker; castration-resistant prostate cancer; enzalutamide; plasma DNA

PMID:
28472366
PMCID:
PMC5834043
DOI:
10.1093/annonc/mdx155
[Indexed for MEDLINE]
Free PMC Article

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