Prevalence of histology-agnostic biomarkers in pure squamous cell carcinomas of the genitourinary tract.

4609 Background: Pure squamous cell carcinomas (SCC) of the genitourinary (GU) tract are less responsive to chemotherapy with limited therapeutic options for systemic disease. SCCs account for 2-8% of bladder cancer cases and treatment mirrors urothelial carcinoma despite significantly lower responses. There are 8 FDA-approved histology-agnostic treatments based on biomarker profiling: dostarlimab (dMMR/MSI-H), pembrolizumab (dMMR/MSI-H; TMB-H), larotrectinib (NTRK fusion), entrectinib (NTRK fusion), selpercatinib (RET fusion), trastuzumab deruxtecan (HER2 positive), and dabrafenib plus trametinib (BRAF V600E mutation). Data are limited on gene alterations associated with SCC of the GU tract. This study aimed to explore the prevalence of biomarkers in pure SCCs of the GU tract. Methods: A retrospective analysis was performed to identify bladder cancer patients with SCCs of the GU tract that underwent comprehensive molecular profiling. Cases were reviewed by a GU pathologist to confirm pure SCC, and biomarker profiling was conducted to assess prevalence of markers with available histology-agnostic treatments as well as areas of potential future exploration through clinical trials. NextGen DNA sequencing (592-gene panel or whole exome) was performed at Caris Life Sciences (Phoenix, AZ). Results: Of 8000 bladder cancer cases, 655 (8.2%) were coded as having components of SCC. After excluding mixed histologies, 275 (2.4%) cases were reviewed by a GU pathologist, and 169 (2.1%) cases of pure SCC of the GU tract were identified. Of these, 88 were females (51.1%) and 81 males (47.9%), with a median age of 70 (range 34-89). Of the histology-agnostic biomarkers with FDA approvals, 45 patients (27%) were TMB-H and 2 patients (1%) harbored dMMR/MSI-H status. No patients harbored NTRK fusions, RET fusions, or BRAF V600E mutations. HER2 IHC data were not available for cases, but ERBB2 mutation was present in 4 patients (2%) and 1 patient (0.6%) had ERBB2 amplification. Other notable mutations included TP53 (70%), pTERT (64%), PIK3CA (30%), CDKN2A (22%), FAT1 (19%), KDM6A (10%), FGFR3 (5%), and PTEN (5%). HRD-associated mutations included BRCA1 (2%), BRCA2 (4%), ATM (4%), PALB2 (1%), CHEK2 (2%), RAD51 (1%), and BRIP1 (1%). AKT mutation was present in 2% of patients. BAP1 was mutated in 3% of patients. Six of 20 (30%) patients were P16+ by IHC. No significant difference in mutation prevalence was observed between specimens from bladder tumors and metastatic sites. Conclusions: This study provides a comprehensive analysis of the genetic landscape of pure SCC of the GU tract that may inform future therapeutic strategies for this rare tumor with limited treatment options. Almost one-third of patients were TMB-High, reflecting a population that may benefit from immune checkpoint inhibitors monotherapy or combination strategies. Other histology-agnostic targets for current therapies were relatively infrequent.