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• W3093551331 abstract "Trimodality therapy (TMT) is a bladder-sparing alternative to radical cystectomy for selected patients with muscle-invasive bladder cancer (MIBC). Molecular determinants of response to TMT are incompletely understood. We sought to characterize the genetic landscape of somatic mutations that distinguish response versus nonresponse to TMT through whole exome sequencing analysis. MIBC patients treated with TMT at a single institution were identified. DNA was extracted from available FFPE pre-treatment transurethral resection of bladder tumor (TURBT) samples, and whole exome sequencing was performed. Sequencing data were analyzed by standard mutation analysis pipelines with a common variant filter to account for lack of matched germline samples. Somatic mutations, insertion/deletions, and copy number variations were identified. Responders (R) were defined as patients with complete response at time of post-treatment TURBT and no recurrence. Nonresponders (NR) were defined as patients with incomplete response at time of post-treatment cystoscopy, those who went on to have a salvage cystectomy, or patients with regional or distant disease progression. Pre-treatment TURBT FFPE samples from 47 TMT patients were successfully sequenced and passed quality control metrics. The median age of the cohort was 69 years and 28% were female. All patients had MIBC (80% T2, 20% T3/T4) and were treated with bladder-sparing chemoradiation, the majority with cisplatin-based chemotherapy. Median follow-up was 6.7 years in alive patients. Twenty-four patients were classified as NR, while 23 were R. Mean somatic tumor mutational burden among R and NR was 13.6 (range, 5.5-24.7) and 12.5 (range, 3.4-26.8) mutations/megabase, respectively (p = 0.22). Exploratory analyses into DNA damage response pathways revealed that more patients classified as R had mutations in genes involved with non-homologous end joining (20/23 pts) compared to NR (11/24) (p<0.001). Specifically, ATM was more frequently mutated in R (n = 6) as compared to NR (n = 3). ERCC2, a gene previously reported to correlate with cisplatin-sensitivity, had somatic mutations in 3 R and 1 NR patient. Our data demonstrates no significant change in mutational burden between R versus NR, suggesting that response to TMT is not associated with hypermutation. Non-homologous end joining DNA repair pathway defects may drive response to conventional chemoradiation, particularly deleterious defects in ATM. These findings warrant validation in larger cohorts." @default.
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• W3093551331 date "2020-11-01" @default.
• W3093551331 modified "2023-09-26" @default.
• W3093551331 title "Mutational Landscape and Genetic Determinants of Response to Trimodality Therapy in Muscle-Invasive Bladder Cancer" @default.
• W3093551331 doi "https://doi.org/10.1016/j.ijrobp.2020.07.430" @default.
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