The most effective therapeutic option for managing nonmuscle invasive bladder cancer (NMIBC), over the last 30 years, consists of intravesical instillations with the attenuated strain Bacillus Calmette-Guérin (the BCG vaccine). This has been performed as an adjuvant therapeutic to transurethral resection of bladder tumour (TURBT) and mostly directed towards patients with high-grade tumours, T1 tumours, and in situ carcinomas. However, from 20% to 40% of the patients do not respond and frequently present tumour progression. Since BCG effectiveness is unpredictable, it is important to find consistent biomarkers that can aid either in the prediction of the outcome and/or side effects development. Accordingly, we conducted a systematic critical review to identify the most preeminent predictive molecular markers associated with BCG response. To the best of our knowledge, this is the first review exclusively focusing on predictive biomarkers for BCG treatment outcome. Using a specific query, 1324 abstracts were gathered, then inclusion/exclusion criteria were applied, and finally 87 manuscripts were included. Several molecules, including CD68 and genetic polymorphisms, have been identified as promising surrogate biomarkers. Combinatory analysis of the candidate predictive markers is a crucial step to create a predictive profile of treatment response. 1. Introduction Thirty years have passed, and intravesical instillations with the attenuated strain bacillus Calmette-Guérin (BCG) are still considered the most effective adjuvant treatment for non-muscle invasive bladder cancer (NMIBC). Generally this treatment is performed adjuvant to transurethral resection of bladder tumour (TURBT) in intermediate and especially high-risk NMIBC, such as, patients with high-grade tumours, T1 tumours, carcinoma in situ (CIS), multiple tumours, large volume tumours, and high rate of prior recurrence tumours [1]. Recent systematic reviews and meta-analysis have shown that BCG therapy contributes to a significant reduction of recurrence and disease progression for high-risk patients and CIS when compared to TURBT alone or intravesical chemotherapy [2–4]. However, several studies demonstrated that from 20% to 40% of the patients fail to respond to this therapeutic, which may result in tumour progression [5–9]. Other important fact related with BCG treatment is that 90% of patients will experience some sort of side effects (local cystitis symptoms such dysuria, frequency alteration, and occasional haematuria) [10, 11] and, for this reason, an elevated number of patients did not
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