Development and Application of Liquid Biopsies in Metastatic Prostate Cancer

Metastatic prostate cancer is a lethal and highly heterogeneous malignancy, associated with a broad spectrum of potentially actionable molecular alterations. In the past decade, disease profiling has expanded to include not only traditional tumor tissue, but also liquid biopsies of cells and genetic material circulating in the blood. These liquid biopsies offer a minimally invasive, repeatable source of tumor material for longitudinal disease profiling but also raise new technical and biological challenges. Here we will summarize recent advances in liquid biopsy strategies and the role they have played in biomarker development and disease management.

Technologies for analysis of circulating tumor cells (CTCs) continue to evolve rapidly, and the latest high content scanning platforms have underscored the phenotypic heterogeneity of CTC populations. Among liquid biopsies, CTC enumeration remains the most extensively validated prognostic marker to date, but other clinically relevant phenotypes like androgen receptor (AR) localization or presence of AR-V7 splice variant are important new predictors of therapy response. Serial genomic profiling of CTCs or circulating tumor DNA (ctDNA) is helping to define primary and acquired resistance mechanisms and helping to guide patient selection for targeted therapies such as poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibition. The era of liquid biopsy-based biomarkers has arrived, driven by powerful new enrichment and analysis techniques. As new blood-based markers are identified, their biological significance as disease drivers must be elucidated to advance new therapeutic strategies, and their clinical impact must be translated through assay standardization, followed by analytical and clinical validation. These efforts, already ongoing on multiple fronts, constitute the critical steps toward more effective precision management of advanced prostate cancer.