(UroToday.com) 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, they utilized a large, real-world cohort to investigate the incidence of a broad array of genetic alterations with potential therapeutic implications at all stages of bladder cancer.
They retrospectively analyzed de-identified NGS data from 1,562 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). Tumor mutational burden was calculated and PD-L1 was assessed by immunohistochemistry. For a subset of patients with tumor-normal match sequencing (n=758), additional incidental germline alterations in 46 different genes were assessed.
A total of 1,562 bladder cancer tumors were investigated: stage I-II (n=165), stage III (n=211), and stage IV (n=1,186). TMB was calculated for 1,428 tumors, and TMB-high (TMB-H; ≥10 mutations per megabase) was noted in 14% of all tumors and similar across tumor stages. PD-L1 positive expression was observed in 33% of tumors with no differences across stages. Microsatellite instability high (MSI-H) status was detected in only 2 (1.2%) stage I-II tumors and 9 (0.8%) 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 915 patients with tumor/normal matched sequencing, they identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%).
In summary, important subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways in all stages. This analysis showed that were is minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.
Presented by: Solomon Woldu, MD, University of Texas Southwestern Medical Center, Dallas, TX
Written by: Stephen B. Williams, MD, MS, FACS, @SWilliams_MD on Twitter, Division of Urology, University of Texas Medical Branch, Galveston, TX; Department of Surgery, University of Texas Medical Branch, Galveston, TX during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain