The role of circulating tumour cells and nucleic acids in blood for the detection of bladder cancer: A systematic review

•Sensitivity and specificity values over 90% were reported using different biomarkers, but many were not validated.•Multi-target panels had higher sensitivity than single biomarkers, without compromising specificity.•Only three studies included validation cohorts.•Prospective studies with validation cohorts are required to test the value of diagnostic biomarkers in bladder cancer. Blood-based biomarkers are a neglected resource in bladder cancer, where the mainstay of focus has been on urinary biomarkers. However, blood-based biomarkers are gaining popularity in other solid cancers, particularly circulating tumour cells (CTCs) and circulating nucleic acids. In this systematic review, we identify and discuss the diagnostic value of CTC, cell-free DNA and RNA based biomarkers in bladder cancer. A MEDLINE/Pubmed systematic search was performed using the following keywords: (bladder cancer) AND (blood OR plasma OR serum) AND biomarker AND (DNA OR RNA OR cfDNA OR cell-free DNA OR RNA OR CTC). All studies including blood-based biomarkers based on DNA, RNA and CTCs were reviewed. Of the included studies, studies reporting sensitivity, specificity and/or AUC/ROC values were further described. Systematic searched yielded 47 studies that were eligible, of which 21, 19 and 3 studies reported DNA, RNA and CTC biomarkers respectively. 15 of these studies included sensitivity, specificity and/or AUC/ROC values. Biomarkers sensitivity and specificity ranged widely at 2.4–97.6% and 43.3–100% respectively. Median number of patients recruited in the studies was 56 (IQR 41–90). Only 3 studies included an independent validation cohort. The highest sensitivity and specificity pairing achieved in the validation cohort was 80.0% and 89.1% respectively. This systematic review provides a comprehensive overview of the blood-based CTC and nucleic acid biomarkers that have been investigated. An overlap in interest of targets between studies suggests that these could be promising biomarkers, but few biomarkers achieve high sensitivity and specificity, and fewer still have been validated independently.