Biomarkers predicting oncological outcomes of high-risk non-muscle-invasive bladder cancer

The European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) scoring systems show limited accuracy for the prediction of disease recurrence and progression of non-muscle-invasive bladder cancer (NMIBC). This aspect is even more relevant in the category of HR NMIBC. Biomarkers might potentially help to further categorize the outcomes of these patients. Therefore, we sought to review the evidence available on tissue-based, urinary, and serum biomarkers for the prediction of recurrence, progression, and survival in HR NMIBC.

A systematic literature review without time restrictions was performed using PubMed/EMBASE, Web of Science, SCOPUS, and the Cochrane Libraries. The search was filtered for articles in the English, Italian, German, French, and Spanish languages, involving patients with more than 18 years of age. Relevant papers on tissue-based, serum and urinary biomarkers related to the prediction of oncological outcomes for high-risk bladder cancer patients were included in the analyses.

Overall, 71 studies were eligible for inclusion in this review. The majority of the investigations performed so far focused on immunohistochemical analyses on tumoral tissue. Overall, p53 was the most studied biomarker, but results regarding its prognostic and predictive role were contradictory. Ki67 seems to be a promising biomarker in the prediction of recurrence. Recently, PD-L1 has been associated with the prediction of recurrence free survival and of treatment-refractory disease. Markers developed un urine samples are focused on commercially available kits, which currently do not unequivocally show strongly superior levels of accuracy to cytology. However, they have demonstrated to be potentially helpful in the prediction of recurrence. Blood-based biomarkers represent an emerging reality with promising future applications.

Despite a long history of attempts to discover accurate biomarkers predicting oncological outcomes for HR NMIBC, contradictory or uncertain findings render the adoption of this ancillary techniques in clinical practice still unlikely. Future attempts should be directed to the development of prospective trials and the definition of standardized cut-off levels to render findings worthy of comparison.