TP53 Y220C mutations in advanced urothelial bladder cancer (UBC): A genomic landscape study.

Abstract

821 Background: TP53 is the most frequently altered gene in human cancers. Novel agents targeting the pathogenic TP53- Y220C mutation and p53-based cancer therapy have attracted significant interest. Evaluation of TP53- Y220C mutation and co-occurrent alterations in UBC is needed. Methods: FFPE tissue from 11,224 UBC patients (pts) underwent hybridization capture and comprehensive genomic profiling. A total of 324 cancer related genes including selected introns of 31 genes frequently rearranged in cancer were evaluated for genomic alterations (GA). We obtained an average sequencing depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were estimated using next-generation sequencing. TMB-high was defined as ≥10 mutations/Mb. PD-L1 expression was measured by IHC (DAKO 22C3). Comparisons were performed using the χ 2 method with Yates correction. Results: TP53 Y220C mutation (Y220C+) was identified in 73 UBC (0.65%). Age/gender were comparable between TP53 Y220C negative (Y220C-) and TP53 Y220C+ pts; 8.4% of TP53 Y220C+ and 8.2% of TP53 Y220C- UBC cases exhibited ≥1 GA. In TP53 Y220C+ UBC, the frequency of co-occurring GA was significantly lower for FGFR3 (8.2% vs 18.3%; P = .038), MTAP loss (13.3% vs 25.1%; P = .035), CDKN2A (26% vs 37.8%; P = .05), and CDKN2B (19.2% vs 30.2%; P = .05) vs TP53 Y220C- UBC. BRCA1 GA was significantly higher in TP53 Y220C+ UBC (8.2% vs 2.0%; P < .0001). In TP53 Y220C+ UBC, trends were observed with numerically higher GA frequency in ERBB2 (20.5% vs 17.6%; not significant [NS]), RB1 (24.7% vs. 21.4%; NS) and numerically lower GA frequencies in TERT (61.1% vs 76.1%; NS), PIK3CA (15.1% vs 21.6%; NS). No significant differences in other GA frequencies: TSC1 (8.2% vs 9.0%, NS), ERBB3 (6.8% to 6.2%, NS), BRCA2 (4.1% to 3.2%, NS), FGFR2 (2.7% to 1.1%, NS), or in MSI / TMB status were detected between groups. PD-L1 low expression (1-49%) was observed in 7.3% of TP53 Y220C+ UBC. Conclusions: The TP53 Y220C mutation is rare in advanced UBC (< 1% of cases). In our study, this mutation was associated with specific co-occurring GA, notably with a significantly lower frequency of FGFR3 and higher BRCA1 GA. TP53 Y220C mutation warrants further clinical investigation in basket trials, including UBC, e.g. NCT04585750. TP53 Y220C+ UBCn=73 TP53 Y220C- UBCn=11,151 p value BRCA1 8.2% 2% <.0001 FGFR3 8.2% 18.3% .038 MTAP 13.3% 25.1% .035 CDKN2A 26% 37.8% .05 CDKN2B 19.2% 30.2% .05 MSI-high 0% 0.7% NS TMB-high 34.2% 34.1% NS