2395P - Micropapillary histology (MPUC) and extra-cellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC)

Background

Given the early promising data with afatinib in advanced UC and the recent approval in NSCLC for anti-HER2 targeted therapy for activating kinase domain exon 20 ERBB2 insertion mutations, there is considerable interest in targeting additional locations in the ERBB2 gene in other tumor types.

Methods

5,485 UBC were sequenced using a hybrid capture based comprehensive genomic profiling assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide mutational signatures and genetic ancestry. PD-L1 tumor cell expression was measured by IHC (Dako 22C3). Statistical comparisons were performed using Fisher’s exact tests with a Bonferonni 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. 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 (pts) with European genetic ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ERBB2 ECD+ UBC had higher frequency of APOBEC signature than ERBB2 WT (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) when compared to ERBB2 WT. The main genomic differences between ERBB2 ECD+ MPUC vs non-MPUC were in frequencies of KMT2D (6.4% vs 27.6%, p=0.02), RB1 (33.3% vs 17.3%, p<.0001) and MTAP GA (11.1% vs 26.9%, p<.0001). PD-L1 expression and MSI-High status (rare overall, 0 - 0.9%), was similar in all three groups.

Conclusions

ERBB2 ECD mutation-driven UBC represents a distinct subtype of UBC featuring an enrichment of MPUC histology from 1-2% to 28% incidence in ERBB2 ECD mutated UBC, and unique clinical and molecular characteristics, including differences in mutational signatures and genetic ancestry. Further exploration of anti-HER2 targeted therapy for non-amp sequence mutations in ERBB2 in UBC appears warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

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). S. Sivakumar: Financial Interests, Personal, Full or part-time Employment, Employment: Foundation Medicine, Inc.; 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. 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. All other authors have declared no conflicts of interest.