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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Date
2017-07-01ICR Author
Author
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
González Del Alba, A
Mellado, B
Fernandez-Calvo, O
Méndez-Vidal, MJ
Climent, MA
Duran, I
Gallardo, E
Rodriguez, A
Santander, C
Sáez, MI
Puente, J
Gasi Tandefelt, D
Wingate, A
Dearnaley, D
PREMIERE Collaborators,
Spanish Oncology Genitourinary Group,
Demichelis, F
De Giorgi, U
Gonzalez-Billalabeitia, E
Attard, G
Type
Journal Article
Metadata
Show full item recordAbstract
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).
Collections
Subject
PREMIERE Collaborators
Spanish Oncology Genitourinary Group
Humans
Disease Progression
Phenylthiohydantoin
Androstenes
Receptors, Androgen
Antineoplastic Agents, Hormonal
Disease-Free Survival
Treatment Outcome
Multivariate Analysis
Proportional Hazards Models
Odds Ratio
Risk Factors
Prospective Studies
Predictive Value of Tests
DNA Mutational Analysis
Mutation
Patient Selection
Time Factors
Adult
Aged
Aged, 80 and over
Middle Aged
Europe
Male
Kaplan-Meier Estimate
Multiplex Polymerase Chain Reaction
Prostatic Neoplasms, Castration-Resistant
Biomarkers, Tumor
Precision Medicine
Circulating Tumor DNA
Research team
Clinical Academic Radiotherapy (Dearnaley)
Treatment Resistance
Language
eng
Date accepted
2017-03-22
License start date
2017-07
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2017, 28 (7), pp. 1508 - 1516
Publisher
OXFORD UNIV PRESS