Blood-based liquid biopsy: insights into early detection, prediction, and treatment monitoring of bladder cancer

Abstract

Bladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.

Keywords: Bladder cancer; Cell-free RNA; Circulating tumor DNA; Circulating tumor cells; Clinical application; Exosomes; Liquid biopsy; Metabolomics; Proteomics.

Fig. 1

Overview of clinical examination methods for bladder cancer and laboratory analytical techniques for liquid biopsies. Routine imaging tests used for bladder cancer detection and diagnosis include X-ray, CT, and PET–CT. Cystoscopy and tissue biopsy are the gold standard for the diagnosis of bladder cancer. Urine cytology is available as a complementary test. Liquid biopsy is emerging as a promising method. Liquid biopsy involves the collection and analysis of five different tumor components from peripheral blood samples: CTCs, cell-free nucleic acids (cfDNA/ctDNA, cfRNA), exosomes, and metabolomics and proteomics. Tumor components are then captured and analyzed in peripheral blood samples using appropriate laboratory assays. CT computed tomography, PET positron emission computed tomography, CTCs circulating tumor cells, ctDNA circulating tumor deoxyribonucleic acid, cfDNA cell-free DNA, cfRNA cell-free RNA

Fig. 2

Overview of the clinical use of liquid biopsy in bladder cancer. Sample analysis of bladder cancer biomarkers early in the disease process allows for early diagnosis and risk stratification. After receiving surgery, liquid biopsy can detect minimal residual disease as a prognostic indicator and allow early detection of recurrent disease. During treatment, liquid biopsy can enhance longitudinal surveillance through its noninvasive approach, thus enabling continuous sampling. In addition, liquid biopsies have the advantage of capturing the entire tumor genome, which can help identify novel genetic markers for targeted therapy and detect treatment resistance

Fig. 3

Comparison of the major liquid biopsy methods in bladder cancer and their main advantages, limitations, clinical applications, and future directions