212P - Mutational landscape and characteristics of ERBB2 in urothelial carcinoma

Background

ERBB2 alterations are potential candidates for targeted treatments in metastatic urothelial cancer (UC). Recent data suggest that HER2-targeted antibody-drug conjugate (ADC) treatment is efficacious. Here, we explore the role of ERBB2 in UC by analyzing genomics in a large database of real-world patients.

Methods

Tumor tissues from 1112 Chinese patients with UC were evaluated by comprehensive genomic profiling for alterations in 808 cancer-related genes. Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements.

Results

Of 1112 cases, 167 (15.0%) featured ERBB2 genomic alterations (GAs), including 82 (7.4%) ERBB2 mutations (ERBB2mut), 41 (3.7%) ERBB2 amplifications (ERBB2amp) and 44 (4.0%) cases had co-occurring ERBB2 GAs. ERBB2mut was not mutually exclusive of ERBB2amp which occurred in up to 43.2% of co-altered cases. The top mutated ERBB2 SNVs/indels were p.S310F/Y (32, 21.2%) and p.L755S (7, 4.6%). ERBB2mut predominantly affected the kinase (49, 32.5%) or extracellular (69, 45.7%) domains. Genes commonly co-altered with ERBB2 were TERT (68.9%), ARID1A(37.1%), RB1 (28.7%), KMT2C (26.9%) and ATM (24.6%). Other significantly higher mutation frequency for genes were TP53, APC, SMARCA4, NF1, ERBB3, ERCC2, EGFR and MTOR (p＜0.05) in ERBB2 GAs cases. Significantly lower rates of CDKN2B were found in ERBB2 GAs compared with ERBB2 wild type (22.0% vs 12.0%, p＜0.01). CDK12 was the most common co-amplification gene with ERBB2amp (p＜0.01). FGFR3 mutations were significantly enriched in ERBB2mut than ERBB2amp (p=0.04). Patients with ERBB2 GAs were significantly more likely to have high tumor mutational burden (p＜0.01).

Conclusions

The study provided the landscape of ERBB2 alterations in UC that may benefit from anti-HER2 agents. Consideration should be given to developing trials inclusive of patients with UC harboring ERBB2 alterations.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.