Predictive Biomarkers of Bacillus Calmette-Guérin Immunotherapy Response in Bladder Cancer: Where Are We Now?

Abstract

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.

FASL polymorphism is associated with response to bacillus Calmette-Guérin immunotherapy in bladder cancer

“…In our most recent systematic review on this subject we point out several markers such as CD68, ezrin, HSP90, CD83, IL2 urinary levels related with BCG response [14]. Several functional polymorphisms in genes such as NRAMP1, hGPX1, XPA, ERCC2 and 6 as well as in genes involved in inflammatory pathways (IL8, TNFA, IL6, TGFB1, COX2, IFNG) [14].…”

“…Still, at the moment there are no reliable biomarkers to determine the outcome of this therapeutics, thereby permitting the early identification of patients better served by alternative therapeutics or cystectomy [14,16]. It has been long thought that such biomarkers may be encountered among molecules/cells involved in the mediation of immune responses at the tumor site [14][15][16].…”

“…Still, at the moment there are no reliable biomarkers to determine the outcome of this therapeutics, thereby permitting the early identification of patients better served by alternative therapeutics or cystectomy [14,16]. It has been long thought that such biomarkers may be encountered among molecules/cells involved in the mediation of immune responses at the tumor site [14][15][16]. Among these putative immune-related biomarkers is the Given the putative involvement Fas/FasL pathway on the immune response, one may hypothesize that functional polymorphisms affecting expression levels of this molecules may deregulate this pathway contributing to the failure of BCG therapeutics [15].…”

“…However, several studies demonstrated that 30% of the patients fail to respond to this therapeutic and in some cases the tumor may become more aggressive [12]. Thus, early identification of patients better served by alternative and/or more aggressive approaches such as cystectomy is a critical aspect in the management of high-risk NMIBC [13,14]. However, at the moment there are no established biomarkers to determine the outcome of BCG immunotherapy.…”

“…However, at the moment there are no established biomarkers to determine the outcome of BCG immunotherapy. Recently, several authors suggest that immunological predictive markers may yield promising clinical value in the context of predicting BCG immunotherapy outcome [14][15][16].…”