The role of functional polymorphisms in immune response genes as biomarkers of bacille Calmette-Guérin (BCG) immunotherapy outcome in bladder cancer: establishment of a predictive profile in a Southern Europe population

Abstract

Objective To evaluate the predictive value of genetic polymorphisms in the context of bacille Calmette‐Guérin (BCG) immunotherapy outcome and create a predictive profile that may allow discrimination of the risk of recurrence. Patients and Methods In a dataset of 204 patients treated with BCG, we evaluated 42 genetic polymorphisms in 38 genes involved in the BCG mechanism of action, using Sequenom MassARRAY® technology. Stepwise multivariate Cox regression was used for data mining. Results In agreement with previous studies we found that gender, age, tumour multiplicity and treatment scheme were associated with BCG failure. Using stepwise multivariate Cox regression analysis we propose the first predictive profile of BCG immunotherapy outcome and a risk score based on polymorphisms in immune system molecules [single nucleotide polymorphisms in tumour necrosis factor α (TNFA)‐1031T/C (rs1799964), interleukin 2 receptor α (IL2RA) rs2104286 T/C, IL17A‐197G/A (rs2275913), IL17RA‐809A/G (rs4819554), IL18R1 rs3771171 T/C, intercellular adhesion molecule 1 (ICAM‐1) K469E (rs5498), Fas ligand (FASL)‐844T/C (rs763110) and TNF‐related apoptosis‐inducing ligand receptor 1 (TRAILR1)‐397T/G (rs79037040)] in association with clinicopathological variables. This risk score allows the categorisation of patients into risk groups: patients within the low‐risk group have a 90% chance of successful treatment, whereas patients in the high‐risk group present a 75% chance of recurrence after BCG treatment. Conclusion We have established the first predictive score of BCG immunotherapy outcome combining clinicopathological characteristics and a panel of genetic polymorphisms. Further studies using an independent cohort are warranted. Moreover, the inclusion of other biomarkers may help to improve the proposed model.

Combination Radiofrequency Ablation and Local Injection of the Immunostimulant Bacillus Calmette–Guérin Induces Antitumor Immunity in the Lung and at a Distant VX2 Tumor in a Rabbit Model

“…The results of the rechallenge test showed that antitumor immunity had been enhanced in the RF/BCG group, but could not suggest the benefits of adding BCG to RF ablation, and the mechanism of immunity enhanced by BCG still needs to be clarified. The strength of immune response is different between rabbit and man, and immunity based on genetic polymorphism is different in each individual (21). However, a combination of RF ablation and local injection of BCG may be capable of activating antitumor immunity, given that previous studies have reported that RF ablation activates antitumor immunity and that BCG is used as an immunostimulant in tumors in clinical practice.…”

Prediction of Bacillus Calmette-Guerin Response in Patients with Bladder Cancer after Transurethral Resection of Bladder Tumor by Using Genetic Variation Based on Genomic Studies

“…However, another study indicated that SNP-174(C/C) at IL-6 was associated with a decreased risk of recurrence (HR = 0.298) and an increased recurrence-free survival (RFS) [14]. Studies on TNF-a polymorphisms reported that the SNP rs1799964(C/C) at TNF-a was associated with a decreased risk of recurrence [6, 15]. Ahirwar et al found that rs4073 (at IL-8 ) was significantly associated with a decreased risk of recurrence ( p < 0.001) and an increased RFS ( p < 0.001) in patients who underwent BCG treatment after TURBT, but these results have not yet been confirmed [13].…”

“…First, genetic alterations in single nucleotides in numerous pathways were found to be closely associated with BCG response. These alterations included single-nucleotide polymorphisms (SNPs), single-nucleotide variations (SNVs), and mutations [5, 6]. Second, various genetic copy number alterations were associated with bladder cancer [7].…”

Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review

“…In addition, efforts should continue to be devoted towards a more comprehensive and integrated understanding of bladder cancer pathways, the tumor microenvironment and cancer-associated immune responses and their influence in treatment response. Namely, future it would be important to ponder possible factors modulating targetmolecules expression and response profile to immunotherapy, such as the highly variable mutational spectrum of bladder cancers [19,180] and inter-patients variability, as translated by our most recent works in the field of pharmacogenetics [181][182][183]. The tumor microenvironment, in particular the immune responses occurring in stroma [184], is another critical aspect that as remained mostly disregarded and warrants careful investigation in the future.…”