(UroToday.com) The 2024 GU ASCO annual meeting featured a urothelial carcinoma rapid oral abstract session, including a presentation by Dr. Michael Basin discussing a comparative genomic landscape study of FGFR3 mutated urothelial carcinoma of the bladder or upper tract.
Activating DNA sequence genomic alterations in the FGFR3 gene, including short variant mutations and kinase domain activating gene rearrangements/fusions, are known drivers and relevant precision treatment targets for patients with urothelial carcinoma. The THOR trial showed a significant overall survival benefit with erdafitinib (an FGFR inhibitor) vs (taxane or vinflunine) in patients with advanced bladder urothelial carcinoma or upper tract urothelial carcinoma.1 Additionally, in the subgroup analyses, patients with upper tract urothelial carcinoma had improved survival with erdafitinib:
Moreover, the PROOF-302 trial showed a higher frequency of FGFR3 genomic alterations in upper tract urothelial carcinoma (30%) vs bladder urothelial carcinoma (13%). Dr. Basin and colleagues aimed to explore differences in the frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered bladder urothelial carcinoma and upper tract urothelial carcinoma.
There were 10,402 bladder urothelial carcinoma and 2,325 upper tract urothelial carcinoma (combined ureter and renal pelvis) specimens that underwent hybrid capture-based comprehensive genomic profiling using a hybrid capture-based to assess all classes of genomic alterations and measure MSI status, tumor mutational burden level, genomic ancestry, genomic signature, germline mutations, and HRD score. PD-L1 was determined by immunohistochemistry, and results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment.
FGFR3 mutation status was significantly more frequent in upper tract urothelial carcinoma than in bladder urothelial carcinoma (24.9% vs 17.7%; p < 0.0001):
Additionally, bladder urothelial carcinoma patients were more often male than upper tract urothelial carcinoma (p = 0.0003). Age (71-72 years), European ancestry (85%), and genomic alterations/tumor (8.9-9.0) were similar between disease location. The number of genomic alterations/case and the frequency of European ancestry were also similar. Targetable genomic alterations in ERBB2 and PIK3CA were more frequent in FGFR3 mutation bladder urothelial carcinoma vs FGFR3 mutation upper tract urothelial carcinoma. Genomic alterations in PTEN, TSC1, and MTAP currently associated with clinical trials were similar in bladder urothelial carcinoma and upper tract urothelial carcinoma. The KEGG ERBB and VEGF signaling pathways were more frequently identified in bladder urothelial carcinoma (p = 0.036) and the MMR pathway more frequently identified in upper tract urothelial carcinoma (p = 0.014). Furthermore, the HRD signature was similar in both groups (2.3-3.1%). Anti-PD(L)1 putative biomarkers included a significantly higher frequency of MSI-high status in upper tract urothelial carcinoma vs bladder urothelial carcinoma but no significant difference in tumor mutational burden or PD-L1 expression levels. As follows are the long-tail plots of genomic alterations in FGFR3 mutated urothelial carcinoma of the bladder and upper tract:
Several limitations of this study include its retrospective design/descriptive nature, selection bias (may not be the same population as the Thor trial), lacking clinical and outcome data, and genomic profiling was performed on a single representative block (heterogeneity not accounted for).
Dr. Basin concluded his presentation discussing a comparative genomic landscape study of FGFR3 mutated urothelial carcinoma of bladder or upper tract with the following take-home points:
- FGFR3 mutation positive status was not significantly more frequent in advanced upper tract urothelial carcinoma compared to bladder urothelial carcinoma
- FGFR3 mutation positive bladder urothelial carcinoma patients had more genomic co-drivers than FGFR3 mutation positive upper tract urothelial carcinoma
- The findings may impact of clinical trial designs for bladder urothelial carcinoma and upper tract urothelial carcinoma, including evaluating combinations of anti-FGFR3 targeted therapies with other agents, including immunotherapies and anti-body drug conjugates
Presented by: Michael Basin, SUNY Upstate Medical University, Syracuse, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Jan 25 – Sat, Jan 27, 2024.
Related content: Comprehensive Genetic Profiling May Optimize Targeted Therapy Selection for FGFR3-Mutated Urothelial Carcinoma Patients - Michael Basin
References:
- Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971.