Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer

• Published in: Targeted oncology 2024-05, Vol.19 (3), p.447-458
• Main Authors: Leary, Jacob B., Enright, Thomas, Bakaloudi, Dimitra Rafailia, Basnet, Alina, Bratslavsky, Gennady, Jacob, Joseph, Spiess, Philippe E., Li, Roger, Necchi, Andrea, Kamat, Ashish M., Pavlick, Dean C., Danziger, Natalie, Huang, Richard S. P., Lin, Douglas I., Cheng, Liang, Ross, Jeffrey, Talukder, Rafee, Grivas, Petros
• Format: Article
• Language: English
• Subjects: Biomedicine; Bladder cancer; Kinases; Medicine; Medicine & Public Health; Mutation; Oncology; Original Research Article
• ISSN: 1776-2596; 1776-260X
• DOI: 10.1007/s11523-024-01056-x

Background Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. Objective To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2 -altered (mutations, amplification) and ERBB2 wild-type UBC. Patients and Methods Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher’s exact tests. Results A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2 wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2 wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2 wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2 wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2 wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2 wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2 wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2 wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2 wt. MSI-high status was more frequent in KDmut+ versus ERBB2 wt, and in ERBB2 wt than in amp+. Conclusions We noted important differences in co-occurring GA in ERBB2 -altered (ECDmut+, KDmut+, amp+) versus ERBB2 wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2 -altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance m