University of Texas Southwestern Medical Center, Dallas, TX
Thomas Gerald , Vitaly Margulis , Xiaosong Meng , Suzanne Cole , Qian Qin , Greg Call , Elizabeth Mauer , Yair Lotan , Solomon L. Woldu
Background: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we used real-world evidence to investigate differences between somatic and germline mutations in localized, early-stage urothelial cancers and advanced urothelial cancers. Methods: We retrospectively analyzed de-identified NGS data from 1,146 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). For the subset of patients with tumor-normal match sequencing (n=758), additional incidental germline alterations in 46 different genes were assessed. Results: A total of 1,146 bladder cancer tumors were investigated: stage I-II (n=124), stage III (n=159), and stage IV (n=863)—summarized in Table. Tumor mutational burden (TMB) was calculated for 1,126 tumors, and TMB-high (TMB-H; ≥10 mutations per megabase) was similar across tumor stages. PD-L1 immunohistochemical staining was performed on 698 tumors, and no significant differences were observed. Microsatellite instability high (MSI-H) status was detected in only 2 (1.6%) stage I-II tumors and 8 (0.9%) stage IV tumors. Alterations—single nucleotide variants, insertions/deletions, and copy number variants—in FGFR2/3, homologous recombination repair genes (18 genes including BRCA1/2 and ATM), additional DNA repair gene mutations (ERCC2, RB1, FANCC) and NTRK fusions were detected at similar frequencies across disease stages. In 758 patients with tumor/normal matched sequencing, we identified a low rate of incidental germline mutations in MUTYH (stage III, 1%; stage IV, 1.9%), BRCA2 (stages I-II, 1.2%; stage III, 1%; stage IV, 0.5%), BRIP1 (stages I-II, 1.2%), ATM (stage III, 1%; stage IV, 0.7%), MSH6 (stage III, 1%; stage IV, 0.2%), and TP53 (stage III, 1%; stage IV, 0.2%). Conclusions: Patients with bladder cancer have similar rates of potentially actionable mutations and genomic landscapes regardless of clinical disease stage. These findings provide a rationale for further investigating targeted therapies among early-stage bladder cancer patients.
Biomarker and Somatic Alterations | Stages I-II (n=124) | Stage III (n=159) | Stage IV (n=863) | p-value | |
---|---|---|---|---|---|
TMB-H | 34/124 (27.4%) | 33/155 (20.8%) | 183/847 (21.2%) | 0.33 | |
MSI-H | 2/124 (1.6%) | 0/157 (0%) | 8/857 (0.9%) | 0.34 | |
PD-L1 Positive | 31/82 (37.8%) | 47/113 (41.6%) | 168/503 (33.4%) | 0.23 | |
FGFR2/3 Mutations/Fusions | 22 (17.7%) | 28 (17.6%) | 158 (18.3%) | >0.99 | |
HRR Gene Mutations | 23 (18.5%) | 28 (17.6%) | 158 (18.3%) | 0.97 | |
Additional DNA Repair Genes | ERCC2 | 3 (2.4%) | 3 (1.9%) | 11 (1.3%) | 0.45 |
RB1 | 20 (16.1%) | 36 (22.6%) | 152 (17.6%) | 0.26 | |
FANCC | 0 (0%) | 0 (0%) | 3 (0.3%) | >0.99 | |
NTRK1/2/3 Fusion | 0 (0%) | 0 (0%) | 2 (0.2%) | >0.99 |
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