The current status and clinical value of circulating tumor cells and circulating cell-free tumor DNA in bladder cancer

Abstract

Urothelial carcinoma of the bladder (UCB) is a complex disease, which is associated with highly aggressive tumor biologic behavior, especially in patients with muscle-invasive and advanced tumors. Despite multimodal therapy options including surgery, radiotherapy and chemotherapy, UCB patients frequently suffer from poor clinical outcome. Indeed, the potential of diverse opportunities for modern targeted therapies is not sufficiently elucidated in UCB yet. To improve the suboptimal treatment situation in UCB, biomarkers are urgently needed that help detecting minimal residual disease (MRD), predicting therapy response and subsequently prognosis as well as enabling patient stratification for further therapies and therapy monitoring, respectively. To date, decision making regarding treatment planning is mainly based on histopathologic evaluation of biopsies predominantly derived from the primary tumors and on clinical staging. However, both methods are imperfect for sufficient outcome prediction. During disease progression, individual disseminated tumor cells and consecutively metastases can acquire characteristics that do not match those of the corresponding primary tumors, and often are only hardly assessable for further evaluation. Therefore, during recent years, strong efforts were directed to establish non-invasive biomarkers from liquid biopsies. Urine cytology and serum tumor markers have been established for diagnostic purposes, but are still insufficient as universal biomarkers for decision-making and treatment of UCB patients. To date, the clinical relevance of various newly established blood-based biomarkers comprising circulating tumor cells (CTCs), circulating cell-free nucleic acids or tumor-educated platelets is being tested in cancer patients. In this review we summarize the current state and clinical application of CTCs and circulating cell-free tumor DNA originating from blood as biomarkers in patients with different UCB stages.

Keywords: Urothelial carcinoma of the bladder (UCB); biomarker; circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); liquid biopsy.

Figure 1

Detection and characterization of circulating tumor cells and circulating tumor DNA, released from primary tumors, recurrences, minimal residual disease and metastases. (A) Several methods to detect and characterize CTCs on protein, mRNA and genomic level have been established and already applied for different tumor entities. Moreover, isolation of viable CTCs is possible and enables cultivation and patient derived xenograft models (PDX). Secretion of proteins by CTCs can be determined by the EPISPOT (EPithelial ImmunoSPOT) assay. Epigenetic alterations can be detected both on CTCs and cell-free ctDNA; (B) approaches and markers for CTC detection already applied for patients with UCB; (C) approaches for ctDNA detection and markers already established for patients with UCB. FISH, fluorescence in situ hybridization; RT-PCR, reverse transcriptase PCR; ICC, immunocytochemistry; CNV, copy number variation; DEL, deletion; INS, insertion; INV, inversion; ITX, intra-chromosomal translocations; CTX, inter-chromosomal translocations.