Urinary biomarkers in muscle-invasive bladder cancer: Current state and open opportunities for neoadjuvant chemotherapy response prediction and patient stratification.

Bladder cancer (BC) is the eleventh most diagnosed malignancy worldwide for both sexes and the sixth in men, representing a significant public health concern. It is a heterogeneous disease classified according to tumor invasion into the bladder wall, currently requiring invasive procedures (such as transurethral resection and biopsy) for accurate tumor-node-metastasis (TNM) cancer staging. Muscle-invasive bladder cancer (MIBC), defined by tumor infiltration into the muscularis propria, represents the most aggressive non-metastatic form. The standard of care for MIBC includes neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) and lymphadenectomy. However, the absence of reliable, non-invasive methods to assess treatment response results in all patients undergoing surgery, regardless of whether a pathological response (pR) has been achieved, heavily compromising their quality of life. Therefore, predictive biomarkers of NAC response are critically needed to guide clinical decisions and personalize therapy. Given the increasing relevance of liquid biopsies, particularly urine-based assays for BC, this review examines the current landscape of urinary biomarkers studied for MIBC stratification and NAC response prediction. Furthermore, we highlight the existing gaps in the field and emphasize the necessity of expanding research into non-invasive urinary biomarkers to enable their future translation into clinical practice.