CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer

Abstract

Prostate cancer is a highly heterogeneous disease, with remarkably different prognosis across all stages. Increased circulating tumor cell (CTC) count (≥ 5) using the CellSearch assay has been identified as one of the markers that can be used to predict survival, with added value beyond currently available prognostic factors. Recently, androgen receptor splice variant 7 (AR-V7) detection has been associated with worse outcomes for patients with castration-resistant prostate cancer (CRPC) treated with novel androgen receptor-signaling (ARS) inhibitors such as abiraterone and enzalutamide but not taxane chemotherapies. Areas covered: In this manuscript, the authors review the available biomarkers in CRPC and discuss emerging data on the value of CTC-derived AR-V7 status to assess prognosis and its potential role to guide treatment selection for patients with advanced prostate cancer. Expert commentary: Current evidence supports AR-V7 status as a prognostic biomarker and also as a potential predictive biomarker for patients with mCRPC. The authors expect that the incorporation of AR-V7 status and other biomarkers (e.g. AR mutations) in the sequential assessment of patients with advanced prostate cancer will lead to a more rational use of available and future therapies, with significant improvements in outcomes for our patients.

Keywords: AR-V7; biomarker; castration-resistant prostate cancer; predictive; prognostic.

Figure 1.. Androgen receptor signaling axis and potential androgen-dependent and independent mechanisms of disease progression.

Figure 1 highlights the androgen receptor (AR)-signaling axis, with conversion of testosterone to dihydrotestosterone (DHT) by the 5α-reductase enzyme, and subsequent AR activation, dimerization, nuclear translocation and activation of transcriptional activation of target genes. The figure summarizes potential mechanisms of resistance to AR-signaling inhibitors by using a schematic representation of a prostate cancer cell. Not shown are multiple additional androgen/AR-independent mechanisms of escape including activated Wnt pathway signaling, loss of the RB1 and/or TP53 genes, overexpression of DNA repair pathways proteins including PARP1 and DNA-PK, epigenetic dysregulation (e.g. via EZH2 overexpression), and neuroendocrine/small cell transformation. Abbreviations: CYP17: cytochrome P450 17alpha-hydroxylase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; PTEN: phosphatase and tensin homolog; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor kappa B; MDM2: mouse double minute 2 homolog; AR-V: AR splice variant; P: progesterone; PR: progesterone receptor; G: glucocorticoid; GR: glucocorticoid receptor.