Pd48-10 Comutations in Fgfr3-Altered Nmibc Influence Recurrence/Progression

You have accessJournal of UrologyBladder Cancer: Non-invasive III (PD48)1 May 2024PD48-10 COMUTATIONS IN FGFR3-ALTERED NMIBC INFLUENCE RECURRENCE/PROGRESSION Neeta D'Souza, Manuel De Jesus Escano, Priya Dave, Syed M. Alam, Sizhi Gao, Xinran Tang, Irina Ostrovnaya, Alvin Goh, Bernard H. Bochner, David Solit, Gopakumar Iyer, Hikmat Al-Ahmadie, and Eugene Pietzak Neeta D'SouzaNeeta D'Souza , Manuel De Jesus EscanoManuel De Jesus Escano , Priya DavePriya Dave , Syed M. AlamSyed M. Alam , Sizhi GaoSizhi Gao , Xinran TangXinran Tang , Irina OstrovnayaIrina Ostrovnaya , Alvin GohAlvin Goh , Bernard H. BochnerBernard H. Bochner , David SolitDavid Solit , Gopakumar IyerGopakumar Iyer , Hikmat Al-AhmadieHikmat Al-Ahmadie , and Eugene PietzakEugene Pietzak View All Author Informationhttps://doi.org/10.1097/01.JU.0001008712.53259.7d.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: FGFR3 is the most altered gene in NMIBC, directly associated with recurrence and inversely associated with progression. Numerous trials that assess the efficacy of FGFR-inhibitors in the treatment of NMIBC have commenced. We postulate that response to these targeted therapies will depend on the presence of co-mutations with FGFR3 in any given tumor. This study seeks to characterize the mutational landscape of FGFR3-altered NMIBC and identify co-mutations that may result in increased risk of recurrence, progression, and treatment resistance. METHODS: From a prospectively maintained database of NMIBC samples sequenced with MSK-IMPACT (a 505-gene targeted exome sequencing panel), we identified 218 samples from 206 patients that were FGFR3-altered. Clinicopathologic characteristics and outcomes, including high grade recurrence-free survival HG-RFS and clinical progression-free survival C-PFS, were assessed via CBioPortal, using a Kaplan-Meier survival analysis. Comutational frequency was assessed via chi-squared analysis; the Benjamini Hochberg procedure was used to determine false discovery (q), and significant p-values were only reported when q<0.05. RESULTS: Of 218 FGFR3-altered tumors, 77% were high-grade. 68% were staged Ta, 31% were T1, and 1% Tis; 90.3% had no evidence of concurrent CIS. We found 6 significant co-alterations that were enriched in FGFR3-mutated tumors (CDKN2A;CDKN2B;KDM6A;STAG2;CREBBP;TERT), and 9 that were mutually exclusive (ERBB2;TP53;RB1;KRAS;RAF1;E2F3;HRAS;ATR;SDHA). Among these co-alteration patterns, we found that HG-RFS was worse in FGFR3-altered tumors with CDKN2A co-altered (Figure 1). When analyzing other cell-cycle genes, we found that co-alteration with CDKN1A was associated with worsened C-PFS, including when restricting our analysis to patients with high-grade NMIBC treated with BCG (Figure 1). Although TP53 is mutually exclusive with FGFR3, in the 34 (15.6%) tumors where FGFR3/TP53 was co-altered, it is associated with worse RFS and C-PFS, even when restricting to BCG-treated patients. CONCLUSIONS: We predict that the diversity of response to FGFR inhibitors in FGFR3-altered NMIBC will be dependent on co-mutational patterns, and identified three co-alterations (CDKN1A, CDKN2A, TP53) that affect the HG-RFS and C-PFS of patients with FGFR3-altered tumors. Download PPT Source of Funding: N/A © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e992 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Neeta D'Souza More articles by this author Manuel De Jesus Escano More articles by this author Priya Dave More articles by this author Syed M. Alam More articles by this author Sizhi Gao More articles by this author Xinran Tang More articles by this author Irina Ostrovnaya More articles by this author Alvin Goh More articles by this author Bernard H. Bochner More articles by this author David Solit More articles by this author Gopakumar Iyer More articles by this author Hikmat Al-Ahmadie More articles by this author Eugene Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...