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Abstract
Detection of androgen receptor (AR) variant 7 (AR-V7) is emerging as a clinically important biomarker in castrate resistant prostate cancer (CRPC). Detection is possible from tumor tissue, which is often inaccessible in the advanced disease setting. With recent progress in detecting AR-V7 in circulating tumor cells (CTCs), circulating tumor RNA (ctRNA) and exosomes from prostate cancer patients, liquid biopsies have emerged as an alternative to tumor biopsy. Therefore, it is important to clarify whether these approaches differ in sensitivity in order to achieve the best possible biomarker characterization for the patient. In this study, blood samples from 44 prostate cancer patients were processed for CTCs and ctRNA with subsequent AR-V7 testing, while exosomal RNA was isolated from 16 samples and tested. Detection of AR and AR-V7 was performed using a highly sensitive droplet digital PCR-based assay. AR and AR-V7 RNA were detectable in CTCs, ctRNA and exosome samples. AR-V7 detection from CTCs showed higher sensitivity and has proven specificity compared to detection from ctRNA and exosomes. Considering that CTCs are almost always present in the advanced prostate cancer setting, CTC samples should be considered the liquid biopsy of choice for the detection of this clinically important biomarker.
Highlights
Advanced prostate cancer (PC) tends to be initially hormone sensitive and is treated with androgen deprivation therapy (ADT)
circulating tumor cells (CTCs) were enumerated and the expression levels of androgen receptor (AR)-FL and AR variant 7 (AR-V7) transcripts were detected in enriched CTC samples using our previously established Droplet Digital PCR (ddPCR) assay [15]
CTCs in blood appear to demonstrate superior stability and we have demonstrated previously that AR-V7 copies can be detected from CTC samples from patient blood drawn in simple EDTA tubes and stored up to 48 h at room temperature, suggesting CTCs either protect the AR-V7 transcript and/or continue to express it in a drawn blood sample [26]
Summary
Advanced prostate cancer (PC) tends to be initially hormone sensitive and is treated with androgen deprivation therapy (ADT). Resistance to first line therapy usually develops in approximately 20–40% of patients, referred to as castrate resistant prostate cancer (CRPC) [1]. PC cells become resistant through molecular changes of the androgen receptor (AR), such as mutations, gene amplification, and, more recently reported, the expression of transcript AR variants [2]. The expression of AR variant 7 (AR-V7), the most abundant and clinically relevant of all variants, has been implicated as a cause of CRPC [3,4]. The translated AR-V7 protein is truncated and lacks the ligand binding domain as well as sequences important for stability and maybe cellular localization [5,6]. Intracellular AR-V7 predominantly localizes to the nucleus and
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