Circulating tumor cells as biomarkers in prostate cancer

Abstract

Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment effects and to identify therapeutic targets in a tumor at the time treatment is being considered. This review focuses on establishing analytically valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The FDA Critical Path provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision-making. CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment, as an efficacy-response surrogate biomarker of survival, is currently being tested in large phase III trials, with the novel antiandrogen therapies abiraterone acetate and MDV3100. Molecular determinants can be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTCs from more patients, the potential clinical uses of CTCs in determining prognosis and monitoring treatment effects, and CTCs as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice.

Figure 1

A clinical states framework for clinical practice, clinical research, and biomarker development in prostate cancer, which is the basis of the National Consensus Criteria for clinical trials in this disease. Adapted from Scher and Heller with permission from Elsevier (17).

Figure 2

Circulating tumor cells in patients with prostate cancer. Sampled by phlebotomy at the time when treatment is being considered, CTC have the potential to provide tumor material for molecular profiling for biomarkers informative of tumor sensitivity to the targeted therapy being considered. FISH images reproduced from Leversha et al (15).

Figure 3

CTC number as a biomarker prognostic of overall survival in patients with CRPC. The estimated median survival time decreased continuously with increasing CTC number, such as Kaplan-Meier estimate of survival calculated from time of CTC draw (A), estimated median survival time based on baseline CTC counts (B) and PSA (C). The symbol (x) represents death times and (o) represents the last follow-up times. Reproduced from Danila et al (34).