Validation and clinical utility of prostate cancer biomarkers

Abstract

To improve future drug development and patient management for patients with castration-resistant prostate cancer (CRPC), surrogate biomarkers that are linked to relevant outcomes are urgently needed. A biomarker must be measurable, reproducible, linked to relevant clinical outcomes, and demonstrate clinical utility. This area is rapidly evolving, with recent trials in patients with CRPC incorporating the detection of circulating tumour cells (CTCs), imaging, and patient-reported outcome biomarkers. We discuss the framework for the development of biomarkers for CRPC, including different categories and contexts of use. We also highlight the requirements of analytical validation, the sequence of trials needed for clinical validation and regulatory approval, and the future outlook for imaging and CTC biomarkers.

Figure 1

Correlation Log (1+CTC) values for 67 patients plotted using CellSearch® and Flow CTC assays. The concordance correlation coefficient is computed to assess the reproducibility of the two assays. With the assays plotted against each other, the concordance correlation coefficient measures the variation of the points around a 45 degree line through the origin. The concordance correlation coefficient for the two assays equals 0.82.

Figure 2

Radionuclide imaging of a patient with castration-resistant prostate cancera | Tc-99m bone scan, b | FDG–PET, c | NaF–PET. Since the three scans are measuring different aspects of osseous metastases, biomarkers unique to each modality must be developed, analytically validated, and tested independently and prospectively before they achieve clinical validity. Abbreviation: FDG, fluorodeoxyglucose.

Figure 3

Larson–Fox–Gonen plot showing SUV_max for individual lesions in a patient at baseline and following 1 month of treatment with a novel anti-androgen, enzalutamide. The Larson–Fox–Gonen plot visually demonstrates changes in lesional uptake for the totality of the patient’s disease burden over time. By using different tracers, one can illuminate the heterogeneity of a patient’s response to treatment pathway by pathway, depending on the tracers used. Shown here are two tracers, ¹⁸FDHT to demonstrate the presence of the androgen receptor, and ¹⁸FDG to demonstrate glucose metabolism. Abbreviations: FDG, fluorodeoxyglucose; FDHT, fluorodihydrotestosterone; SUVmax, standardized uptake value (maximum).

Figure 4. Identifying CTCs using CellSearch®

The CellSearch® system uses a glass-surfaced cartridge. Immunomagnetically labelled cells expressing EpCAM are fluorescently stained and pulled to the surface of the chamber using a targeted magnetic field. a | The semiautomated imaging system captures four fluorescent images at each of 175 locations in order to create a 4-composite photograph of the entire surface of the chamber. b | A close-up of approximately 25 of the 175 locations, showing a large number of fluorescently labelled events present within each location. c | The CellTracks® software analyzes individual events in the image frames, creating a gallery of images including only those events where DAPI and cytokeratin fluorescence are co-located. The user examines these events for the presence of DAPI (purple), cytokeratin (green), and the absence of CD-45 (red) fluorescence. Events that meet the criteria of a CTC assay based on morphology, an intact nucleus, and cytokeratin expression, and which are negative for CD-45 expression (events boxed in red), are only a proportion of cytokeratin-positive events in the chamber. Other events (not boxed) that do not meet these criteria are not scored as CTCs. Permission obtained from Robert McCormack, Veridex, LLC. Abbreviations: CTC, circulating tumour cell; DAPI, 4′,6-diamidino-2-phenylindole. (Image courtesy of Robert McCormack, Veridex, LLC.)