Date Published: August 7, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Luís Lima, Mário Dinis-Ribeiro, Adhemar Longatto-Filho, Lúcio Santos.
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.
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 .
A systematic review was conducted through a MEDLINE database (PubMed) search, in order to retrieve papers linking biomarkers associated with BCG treatment outcome, available online in July 2011, using the following query: ((“Urinary Bladder Neoplasms”[Mesh] OR “bladder cancer”[All Fields] OR “superficial bladder cancer”[All Fields]) AND (“BCG Vaccine”[Mesh] OR “bcg”[All Fields] OR “bcg treatment”[All Fields] OR “BCG immunotherapy”[All Fields] OR “BCG therapy”[All Fields] OR “intravesical therapy”[All Fields] OR “Bacillus Calmette-Guérin”[All Fields])) AND (“Neoplasm Recurrence, Local”[Mesh] OR “recurrence”[All Fields] OR “outcome”[All Fields] OR “treatment failure”[All Fields]).
Using the criteria defined in the material and methods section several biomarkers related with BCG treatment have been identified and organized according to their biological nature. This information has been comprehensively summarized in Tables 1, 2, and 3. In particular, Table 1 refers to molecular characteristics evaluated in the tumour prior to treatment, Table 2 refers to urinary markers measured during treatment, and Table 3 compiles information about genetic polymorphism evaluated in the context of BCG treatment response. The most promising biomarkers are presented in more detail the following sections.
Several studies were conducted to personalize and improve the NMIBC treatment with BCG. A plethora of exciting data has emerged recently, which represents a potential tool to define differences in BCG treatment response.
Regarding the tumour molecular characteristics studied, three major conclusions can be drawn, p53 and ki-67 are not suitable predictive biomarkers, markers such as TAMs and other molecules (ezrin, HSP90, CD83, and Cox2) require validation, and different approaches such as gene expression and epigenetic alterations of the tumour prior to treatment may bring new insights in the search for predictive biomarkers of BCG immunotherapy.