Dataset Information

Plasma Androgen Receptor in Prostate Cancer.

ABSTRACT: The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

SUBMITTER: Conteduca V

PROVIDER: S-EPMC6896184 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Plasma Androgen Receptor in Prostate Cancer.

Conteduca Vincenza V Gurioli Giorgia G Brighi Nicole N Lolli Cristian C Schepisi Giuseppe G Casadei Chiara C Burgio Salvatore Luca SL Gargiulo Stefania S Ravaglia Giorgia G Rossi Lorena L Altavilla Amelia A Farolfi Alberto A Menna Cecilia C Colangione Sarah Pia SP Pulvirenti Mario M Romeo Antonino A De Giorgi Ugo U

Cancers 20191104 11

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in ...[more]

PMID: 31689899

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Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Project description:BACKGROUND:Prostate cancer (PRCA) is an androgen-driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR-targeted therapies, there has been a rising interest in the expression of full-length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes. METHODS:Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full-length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning-based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments. RESULTS:Full-length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double-positive (AR+ /ARv7+ ) population in metastases compared to benign, and an increase of the double-negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double-positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double-negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years. CONCLUSIONS:Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.

Dataset Information

Plasma Androgen Receptor in Prostate Cancer.

Publications

Plasma Androgen Receptor in Prostate Cancer.

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