Androgen receptor expression is associated with prostate cancer‐specific survival in castrate patients with metastatic disease

Abstract

prostatectomy and 61 prostate needle biopsy samples), were independently reviewed; H&E morphometry and quantitative immunofluorescence were used to assess the samples. Sections were analysed with a multiplex quantitative immunofluorescence (IF) assay for cytokeratin-18 (epithelial cells), 4 ′ ,6-diamidino-2-phenylindole (nuclei), p63/high molecular weight keratin (basal cells), AR and α -methyl CoA-racemase. Images were acquired with spectral imaging software and processed for quantification with IF algorithms. RESULTSThe median follow-up was 12 years from diagnosis; 49 men (47%) baseline PSA levels of ≥ 20 ng/mL, 55 (53%) had a Gleason sum of 8, 63 (60%) died from the disease and 40% were alive (censored). In all, 66 patients had evaluable IF features, and the association with outcome was evaluated by univariate Cox modelling and support-vector regression. PSA was the only clinical variable associated with outcome (concordance index, CoI, 0.41; P < 0.05, log-rank test). The amount of AR present within tumour nuclei (regardless of tissue provenance and primary treatment) significantly correlated with a greater risk of a shorter time to prostate cancer-specific mortality (CoI 0.36; P < 0.05 log-rank test). There were no H&E features that correlated with mortality. CONCLUSIONBy univariate analysis, increased nuclear AR expression in either the diagnostic biopsy and/or radical prostatectomy specimen, from patients with advanced disease, was associated with a reduced time to prostate cancer-specific mortality. KEYWORDSandrogen receptor, prostate cancer, progression, systems pathology Study Type -Aetiology (case series) Level of Evidence 4 OBJECTIVETo investigate whether baseline (before treatment) clinical variables and tumour specimen characteristics (including the androgen receptor, AR) from patients with castrate-resistant metastatic prostate cancer can be used to predict the time to prostate cancer-specific mortality and overall survival, as AR levels in prostate cancer have been associated with disease progression, including prostate-specific antigen (PSA) recurrence and systemic metastasis. PATIENTS AND METHODSHaematoxylin and eosin (H&E) slides/blocks and outcome data from a 104 castrate patients with metastatic disease (43 INTRODUCTIONThe growth of prostate cancer is the result of androgen signalling through the androgen receptor (AR), with primary treatment for recurrence including LHRH agonists, ligand blockade, inhibition of receptor activation and orchidectomy [1,2]. However, the response is variable, and dependent on stage, previous therapy and individual tumour characteristics. Although initially successful, the cancer eventually progresses to an androgen-resistant state which heralds the development of a malignant phenotype. In addition to castrate PSA secretion, several studies have documented molecular events, including mutations and amplification of the AR gene and hyper-activation of AR signalling [2].Recent evidence has shown that AR RNA and protein in the primary radical prostatectomy (RP) sampl...

Nuclear factor κB predicts poor outcome in patients with hormone-naive prostate cancer with high nuclear androgen receptor

“…7B). This further supports our assertion that high AR-expressing patients represent a subgroup of patients with PCa, at higher risk for malignant progression than low AR expressers [25,26]. The association between Ki-67 and disease-specific survival was independently significant when entered into multivariate analysis along with age, Gleason sum, clinical stage, presence of metastases, and PSA level at diagnosis: P = .011; HR, 4.3.…”

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

“…The data herein provide a mechanism by which AR overexpression is achieved in CRPC, as mediated by loss of RB function and/or deregulation of E2F1. This is of significance, as forced AR deregulation alone is sufficient to induce CRPC transition in tumor models (23), and high AR levels are strongly correlated with increased risk of death from PCa (24). Thus, the present findings suggest that aberrations in RB promote PCa progression and is associated with lethal tumor phenotypes.…”

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naïve prostate cancer and are elevated in castration-resistant disease

“…High expression levels of the AR protein in patients treated with radical prostatectomy before ADT have been associated with worse overall and disease-specific survival and shorter time to disease relapse (reviewed in Donovan et al (2008Donovan et al ( , 2010 and Hodgson et al (2012)). We showed a similar finding for patients with locally obstructive HN PC treated by palliative TURP.…”