The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2/HER2 Expression


Agreen Hadadi1, Harris Krause2, Andrew Elliott2, Alex Farrell2, Jacqueline Brown1, Bassel Nazha1, Bradley Carthon1, Chadi Nabhan2, Pedro Barata3,4, Mohamed Saleh5, Yuanquan Yang5, W. Michael Korn2, Rana R. McKay6, Mehmet A Bilen1

Background: Human epidermal growth factor receptor 2 (HER2) expression has been associated with poor prognosis in urothelial carcinoma (UC). Recent data suggests that HER2-targeted antibody-drug conjugate (ADC) treatment is efficacious. Here, we explore the role of ERBB2/HER2 expression in UC by analyzing genomic and clinical outcomes in a large database of real-world patient samples.

Methods: NextGen Sequencing (NGS) of DNA (592 genes or whole exome sequencing; WES)/RNA (whole transcriptome sequencing; WTS) was performed for 4,743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 (SP142; Positive (+): ≥ 2+, ≥ %5) and HER2 (4B5; +: ≥3+ and >10%) expression was tested by IHC. High tumor mutational burden (TMB-high) was defined as ≥10 mutations/MB. ERBB2-high and -low expression were defined as ≥ top and < bottom quartile of ERBB2 transcripts per million (TPM), respectively. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons (< .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patients.

Results: 2.5% (120/4743) of tumors had HER2 IHC and WTS data available, 97% (61/63) of HER2+ tumors were ERBB2-high, and 98% (51/52) were ERBB2-amplified by DNA NGS (copy number ≥4; 77% with copy number ≥6). Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), < .001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = .95) but significantly higher in lung metastases (59 v 47 mTPM, p < .001). Mutation rates of ERRB2 (12%), pTERT (76%) and ELF3 (14 %) were higher in ERBB2-high compared to ERBB2-low tumors (5%, 60%, 5%, all p < .001). The opposite pattern was observed for CDKN2A (4% ERBB2-high, 9% ERBB2-low), KMT2D (20%, 35%) and PIK3CA (13%, 23%) (all p < .001). There was a higher incidence of PD-L1+ staining in ERBB2-low (40.3%) compared to ERBB2-high tumors (18%, p < .001). 45.4% of ERBB2-high tumors were TMB-high compared to 35% of ERBB2-low (p < .001). ERBB2-high tumors had higher expression of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) compared to ERBB2-low (each, p < .001). ERBB2-high tumors were associated with better overall survival from time of tissue sampling than ERBB2-low (HR 1.34, 95% CI 1.14-1.60, p < .001) and from start of anti-PD-L1 therapy (HR 2.26, 95% CI 1.02-5.02, p = .04) but no difference in OS from start of anti-PD1 therapy (HR 1.39, 95% CI 0.75-2.58, p = .30).

Conclusions: High concordance between HER2 IHC and ERBB2 expression/amplification was observed. Differences in the genomic landscape and ADC target expression of ERBB2-high vs -low UC may provide rationale for combination treatment strategies with HER2-blocking antibodies. The association between high ERBB2 expression and survival advantage warrants further investigation.

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