Pd14-07 Ercc2 Alterations Are Associated With Enhanced Sensitivity to Intravesical Bacillus Calmette-Guérin in High-Grade Non-Muscle Invasive Bladder Cancer

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-07 ERCC2 ALTERATIONS ARE ASSOCIATED WITH ENHANCED SENSITIVITY TO INTRAVESICAL BACILLUS CALMETTE-GUÉRIN IN HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER Muneeb Alam, Jacob E. Tallman, Florestan Koll, Neeta D'Souza, Timothy Donahue, Alvin Goh, Judy Sarungbam, Michael Berger, Nikolaus Schultz, Gopa Iyer, David B. Solit, Bernard H. Bochner, Hikmat Al-Ahmadie, and Eugene J. Pietzak Muneeb AlamMuneeb Alam , Jacob E. TallmanJacob E. Tallman , Florestan KollFlorestan Koll , Neeta D'SouzaNeeta D'Souza , Timothy DonahueTimothy Donahue , Alvin GohAlvin Goh , Judy SarungbamJudy Sarungbam , Michael BergerMichael Berger , Nikolaus SchultzNikolaus Schultz , Gopa IyerGopa Iyer , David B. SolitDavid B. Solit , Bernard H. BochnerBernard H. Bochner , Hikmat Al-AhmadieHikmat Al-Ahmadie , and Eugene J. PietzakEugene J. Pietzak View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: ERCC2 is a nucleotide excision repair gene that is frequently mutated in bladder cancer. It is hypothesized that alterations in ERCC2 will lead to increased tumor mutational burden (TMB) and neoantigen load, which will sensitize bladder tumors to immunogenic therapies such as Bacillus Calmette-Guérin (BCG). The purpose of this study is to evaluate the association between ERCC2 alteration status and outcomes following intravesical BCG in high-grade non-muscle invasive bladder cancer (NMIBC). METHODS: Patients diagnosed with high-grade NMIBC who underwent targeted exome sequencing with a 505 gene panel were identified. Patients receiving at least five induction doses of intravesical BCG were selected, and pretreatment tumors with available sequencing data were included in the analysis. Specimens were excluded if no somatic mutations were present (n=13). Tumor mutational burden was compared between ERCC2-altered (-alt) and ERCC2-wild type (-wt) tumors using the Wilcoxon rank-sum test. Survival analysis was performed with the Kaplan-Meier method using the log-rank test to determine recurrence-free (RFS) and progression-free survival (PFS) based on molecular features. RESULTS: A total of 267 patients were identified for analysis. Median age was 70.1 years (IQR 62.3, 76.6) and 72 (27.0%) patients were female. The cohort included 31 (11.6%) Tis, 112 (41.9%) Ta, and 124 (46.4%) T1 tumors with a carcinoma in situ component present in 93 (34.8%) samples. Median follow-up was 34.2 months (IQR 19.9, 62.5). ERCC2 alterations were noted in 55 (20.6%) patients, the majority of which had N238S missense mutations (72.7%). ERCC2-alt tumors had an increased median TMB compared to ERCC2-wt tumors (27.2 vs. 7.9 mut/mB, p<0.001). ERCC2 alterations were associated with improved RFS (HR 0.52, p=0.019) after BCG. TMB ≥10 mut/mB was also associated with improved RFS (HR 0.55, p=0.004), and this effect was pronounced in the ERCC2-alt cohort (HR 0.29, p=0.046). ERCC2 alterations were associated with improved PFS, but this was not statistically significant (HR 0.30, p=0.084). CONCLUSIONS: Alterations in the DNA damage repair gene ERCC2 are associated with genomic instability and enhanced sensitivity to intravesical BCG. These findings warrant prospective validation to clarify the role of ERCC2 as a biomarker of response to BCG. Source of Funding: The Sidney Kimmel Center for Prostate and Urologic Cancers at MSKCC, NIH/NCI Cancer Center Support Grant (P30CA008748), NIH/NCI R01/R37CA276946, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, NCI Specialized Programs of Research Excellence (SPORE) in Bladder Cancer (P50CA221745), Cycle for Survival, Bladder Cancer Advocacy Network Young Investigator Award, Ruth L. Kirschstein T32 National Research Service Award © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e356 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Muneeb Alam More articles by this author Jacob E. Tallman More articles by this author Florestan Koll More articles by this author Neeta D'Souza More articles by this author Timothy Donahue More articles by this author Alvin Goh More articles by this author Judy Sarungbam More articles by this author Michael Berger More articles by this author Nikolaus Schultz More articles by this author Gopa Iyer More articles by this author David B. Solit More articles by this author Bernard H. Bochner More articles by this author Hikmat Al-Ahmadie More articles by this author Eugene J. Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...