Liquid biopsies for bladder cancer

Abstract

The development of accurate urinary biomarkers for the non-invasive detection of urothelial bladder cancer (UBC) could transform patient pathways by reducing reliance on cystoscopy, and the identification of highly prognostic (or even predictive) biomarkers could better guide patient management. A number of approaches are being utilised to address these challenges in both urinary- and plasma-borne tumour DNA (tDNA), so-called "liquid biopsies". Next generation sequencing (NGS) and droplet digital PCR (ddPCR) allow detection of very low levels of such tDNA amongst a large excess of non-tumour DNA, the former permitting large mutation panels to be assessed and the latter potentially identifying ultrarare mutant alleles yet restricted for multiplexing. Christensen et al. recently published their data regarding a ddPCR approach for the detection of common FGFR3 and PIK3CA mutations in urinary cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA). In this proof-of-principle study, levels of mutant cfDNA in the urine of non-muscle-invasive bladder cancer (NMIBC) patients were shown to be positively correlated with tumour stage, grade and size, and a high initial level of mutant urinary cfDNA indicated future disease progression. In a cystectomy patient group, high mutant urinary cfDNA predicted future disease recurrence, the association being more pronounced with ctDNA. In this Perspective, we discuss these data in more detail and in parallel with the study's limitations. We set these findings within the context of the field as a whole, highlighting important data from other groups, the strengths and weaknesses of alternative approaches, and the exciting and potentially significant future utilities of these techniques.

Keywords: Liquid biopsy; bladder cancer; urinary biomarker.

Figure 1

Illustration of how a therapy may eradicate the predominant clone within a tumour (clone 1, green), accompanied by tumour shrinkage, yet in parallel a potentially more aggressive treatment-resistant clone thrives (clone 2, red). It is feasible that genome-wide or panel-based approaches to the analysis of urinary or plasma tDNA during treatment may demonstrate such phenomena and could be performed regularly, whereas one would not invasively biopsy a bladder tumour on a regular basis to identify the same phenomena. A liquid biopsy may also capture disease heterogeneity better than a solid biopsy which only samples a single part of a single tumour. Clearly, in vivo, the scenario is far more complex with multiple clones within the same tumour vying for survival, and so this illustration is a gross oversimplification.