Extracellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC).

Abstract

566 Background: Given the recent approval in lung cancer for the first anti-HER2 targeted therapy directed against activating kinase domain exon 20 ERBB2 insertion mutations, considerable interest has arisen in targeting additional locations in the ERBB2 gene in other tumor types. Methods: 5,485 UBC samples were sequenced using a hybrid capture-based comprehensive genomic profiling (CGP) assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide signatures and predominant genetic ancestry. Statistical comparisons utilized the Bonferroni correction. Results: 548 (10.0%) of UBC featured ERBB2 gene amplification (amp) and 219 (4.0%) featured an ERBB2 ECD+ sequence mutation (74% S310F and 26% S310Y). ERBB2 ECD+ mutations and ERBB2 amplification were mutually exclusive. 16.4% of ERBB2 ECD+ UBC had more than one E RBB2 sequence mutation. Central pathology review of the 219 ERBB2 ECD+ UBC revealed that 63 (28.8%) featured a micropapillary histologic appearance (MPUC). ERBB2 ECD+ UBC featured more patients with European ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ECD mut+ UBC also featured lower association with African ancestry than ERBB2 amp (2.7% vs 7.8%; p=.04) and lower frequency of gLOH > 16% (9.3% vs 19.1%; p=.04). MSI-High status was similar and rare in all 3 groups (range 0 to 0.9%). ERBB2 ECD+ UBC had a higher frequency of APOBEC signature than ERBB2 amp (82.9% vs 72.4%; p=.03). TMB > 10 mut/mb was higher in ERBB2 amp (49.2% vs 31.4%; p<.0001) and ERBB2 ECD+ (59.8% vs 31.4%; p<.0001) compared to ERBB2 WT as was the mean TMB (11.8 and 17.4 mut/Mb respectively vs 8.9 mut/Mb, p<0.001 for both). Among important UBC individual genes, FGFR3 GA were significantly higher in ERBB2 WT than both ERBB2 amp (19.9% vs 6.2%; p<.0001) and ERBB2 ECD+ (19.9% vs 10.5%; p=.0002). CDKN2A GA were significantly higher in ERBB2 amp (39.1% vs 27.9% ERBB2 WT; p<.0001) only. The higher frequency of KMT2D GA in MPUC+ ECD+ and MPUC- ECD+ UBC (63.4% vs 27.6%; p=.02) was the only genomic difference between these cohorts. Conclusions: ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.