A Stepping Stone Toward Personalized Oncology: Genomic Analysis of Circulating Tumor Cells to Guide Management of Metastatic Castration-resistant Prostate Cancer.

With the advent of novel, life-prolonging hormonal and chemotherapies, the treatment of metastatic castrationresistant prostate cancer (mCRPC) has dramatically changed in recent years. Abiraterone acetate and enzalutamide both target the androgen receptor (AR) and block downstream androgen-mediated signaling in cancer cells, whereas cabazitaxel—a novel taxane chemotherapeutic— works much like docetaxel to impair microtubule function in cancer cells. In addition, a number of other hormonal agents (ARN-509, galeterone, ODM-201) are under investigation for the treatment of mCRPC [1]. In an era of evergrowing therapeutic options, a major challenge facing clinicians is determining which agent is most appropriate for an individual patient. Predictive biomarkers can address this need and provide information specific to an individual patient. In recent years, the detection and analysis of circulating tumor cells (CTCs) has been shown to have clinical utility in prostate cancer, both as a marker for overall prognosis [2] and as a surrogate end point for clinical trials [3]. Yet, until recently, most studies focused primarily on the enumeration of CTCs and did not use the molecular and genotypic information contained within these cells to inform clinical decision making. Advances in CTC-capture technology, along with improvements in the reliable analysis of small inputs of DNA and RNA, have allowed researchers to understand more qualitative information from an individual patient’s CTCs. These advances in CTCmolecular and genetic analysis were recently shown to have promise for understanding treatment resistance to novel AR-targeting therapies [4]. To understand how CTCs can provide important clinical information about the AR-signaling axis, it is important to note that most prostate cancers develop resistance to androgen deprivation therapy through the development of genetic changes, such as AR amplification, AR mutation, or intracrine androgen synthesis [5–7], which allow for maintenance of AR signaling in the castrate environment. One resistance mechanism under active investigation is alternativeAR splicing [8]. In thismechanism, a change in the processing of the full-length AR messenger RNA leads to the development of a constitutively active splice-variant AR protein that lacks the androgen binding domain but retains the ability to bind to the cell’s DNA to promote cell growth and survival (Fig. 1). A recent study [4] showed that detection of a specific AR splice variant, termed AR-V7, in CTCs of men with mCRPC was highly predictive of resistance to both abiraterone acetate and enzalutamide. Men with AR-V7– positive CTCs did not have prostate-specific antigen (PSA) responses to either of these hormonal agents and had shorter progression-free survival (PFS) and overall survival (OS) comparedwithmenwhodid not have detectable AR-V7. This finding suggested that the presence of AR-V7 in CTCsmay be a useful predictive biomarker to guide the choice of whether to use hormonal agents in this population. A major question that arose from this work is whether the presence of AR-V7 is simply a marker of an aggressive disease process and overall poor prognosis. To answer this question, in this month’s issue of European Urology, Onstenk et al evaluated the association of AR-V7 inmCRPC CTCswith response to the taxane chemotherapeutic cabazitaxel [9]. E U RO P E AN URO L OG Y 6 8 ( 2 0 1 5 ) 9 4 6 – 9 4 8