Open AccessGenomic Biomarkers and Underlying Mechanism of Benefit from BCG Immunotherapy in Non-Muscle Invasive Bladder Cancer
Author(s) -
Diogo Assed Bastos,
Rômulo Loss Mattedi,
Rodrigo Barreiro,
Fernanda Oliveira Santos,
Vanessa Candiotti Buzatto,
Cibele Masotti,
Jussara Michaloski Souza,
Mariana Zuliani Theodoro de Lima,
Giulia W. Friguglietti,
Carlos Dzik,
Denis Leonardo Fontes Jardim,
Rafael Ferreira Coelho,
Leopoldo RibeiroFilho,
Maurício Cordeiro,
William C. Nahas,
Evandro S. de Mello,
Roger Chammas,
Luiz F. L. Reis,
Fabiana Bettoni,
Pedro A. F. Galante,
Anamaria A. Camargo
Publication year - 2020
Publication title -
bladder cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.27
H-Index - 19
eISSN - 2352-3735
pISSN - 2352-3727
DOI - 10.3233/blc-200289
Subject(s) - medicine , bladder cancer , immunotherapy , biomarker , oncology , cohort , cancer , exome sequencing , gene , mutation , biology , genetics
BACKGROUND: Optimal therapy for high-risk non-muscle invasive bladder cancer (NMIBC) includes intravesical instillation of Bacillus Calmette-Guérin (BCG). However, about 25-45% of patients do not benefit from BCG immunotherapy, and there is no biomarker to guide therapy. Also, many questions regarding BCG mechanisms of action remain unanswered. OBJECTIVE: To identify genomic biomarkers and characterize the underlying mechanism of benefit from BCG in NMIBC. PATIENTS AND METHODS: Pre-treatment archival index-tumors of 35 patients with NMIBC treated with BCG were analyzed by whole-exome sequencing (WES). Tumor mutation burden (TMB) and neoantigen load (NAL) were correlated with BCG response rate (RR) and recurrence-free survival (RFS). The presence of deleterious mutations in DNA damage response (DDR) genes was also compared between BCG-responsive (BCG-R, N = 17) and unresponsive (BCG-UR, N = 18) subgroups. RESULTS: TMB and NAL were higher in BCG-R compared to BCG-UR patients (median TMB 4.9 vs. 2.8 mutations/Mb, P = 0.017 and median NAL 100 vs. 65 neoantigens, P = 0.032). Improved RR and RFS were observed in patients with high vs. low TMB (RR 71% vs. 28%, P = 0.011 and mRFS 38.0 vs. 15.0 months, P = 0.009) and with high vs. low NAL (RR 71% vs. 28%, P = 0.011 and mRFS 36.0 vs. 18.5 months, P = 0.016). The presence of deleterious mutations in DDR genes was associated with improved RFS (mRFS 35.5 vs. 11.0 months, P = 0.017). CONCLUSIONS: In our cohort, improved outcomes after BCG immunotherapy were observed in patients with high TMB, high NAL and deleterious mutations in DDR genes. BCG may induce tumor-specific immune response by enhancing the recognition of neoantigens.