2400P - Frequency and nature of genomic alterations (GA) in ERBB2-altered urothelial bladder cancer (UBC)

Background

ERBB2 overexpression is an oncogenic driver in many solid tumors, including UBC. Activating mutations (mut) in ERBB2 gene were shown to play an oncogenic role relatively like ERBB2 amplification (amp). We describe and compare the frequency and nature of GA of ERBB2-altered (mut, amp) and ERBB2 wildtype (wt) UBC.

Methods

Using a hybrid capture based comprehensive profiling (CGP) assay, 9,518 UBC cases were evaluated for all classes of GA, tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by IHC (Dako 22C3). Statistical comparisons were performed using Fisher’s exact tests.

Results

602 (6.3%) UBC featured ERBB2 extra-cellular domain (ECD) short variant (SV) GA (ECDmut), 253 (2.7%) UBC featured ERBB2 kinase domain (KD) SV GA (KDmut); 866 (9.1%) had ERBB2 amp; 7,797 (81.9%) UBC were ERBB2wt. The GA/tumor was higher in all ERBB2 GA groups vs ERBB2wt. European genetic ancestry of ECDmut+ was higher than ERBB2wt (p=.02). CDKN2A/MTAP loss were more frequent in ERBB2wt vs ECDmut and amp only (both p<.0001). ERBB3 GA was more frequent in ECDmut and KDmut than ERBB2wt (both p<.0001). TERT GA were more frequent in ECDmut, KDmut and amp vs ERBB2wt (all p<.0001). TOP2A amp and TP53 SV GA were significantly higher in ERBB2 amp vs ERBB2wt, ECDmut and KDmut (p<.0001). Mean TMB levels were significantly higher in ECDmut, KDmut and amp than in ERBB2 wt (all comparisons p<.0001). APOBEC signature was more frequent in ECDmut, KDmut and amp vs ERBB2wt (p<.0001). No significant differences in PD-L1 status, MSI-high or gLOH between altered & wt subgroups. The table summarizes key findings. Table: 2400P

Conclusions

We noted important differences in co-occurrent-GA in ERBB2-altered (ECDmut, KDmut, amp) vs wt UBC, and higher mean TMB and higher APOBEC mut signature in the ERBB2-altered group. Results can help refine future clinical trial designs and help elucidate possible resistance mechanisms for ERBB2-altered UBC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Steering Committee Member: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Coordinating PI: Incyte; Financial Interests, Local PI: Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). A. Kamat: Financial Interests, Personal, Advisory Board: Merck, Seagen, AstraZeneca, Janssen, CG Oncology, Astellas, Ferring; Financial Interests, Personal, Officer: International Bladder Cancer Group (IBCG); Financial Interests, Institutional, Advisory Board: CyPRIT; Non-Financial Interests, Leadership Role: IBCG, IBCN; Non-Financial Interests, Member of Board of Directors: AUA; Non-Financial Interests, Advisory Role: EAU. D.C. Pavlick, D.I. Lin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine. N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche LTd. R. Huang: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Bristol Myers Squibb, Asieris Pharmaceuticals, Merck KGaA, Seattle Genetics, Aadi Bioscience, Pfizer, Janssen, Boston Gene, Mirati Therapeutics, Exelixis, Genentech/Roche, Gilead Sciences, CG Oncology, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, ImmunityBio, Lucence Health, G1 Therapeutics, Fresenius Kabi, Guardant Health, PureTech, Regeneron Pharmaceuticals, Strata Oncology, Urogen, Silverback Therapeutics, Astellas Pharma; Financial Interests, Institutional, Local PI: Pfizer, Clovis Oncology, Bavarian Nordic, Gilead Sciences, Bristol Myers Squibb, Debiopharm Group, MSD, QED Therapeutics, Merck KGaA, GSK, Mirati Therapeutics, G1 Therapeutics. All other authors have declared no conflicts of interest.