Introduction:

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase encoded by the gene ERBB2 that is associated with tumorigenesis. The frequency of ERBB2 mutations in bladder cancer is higher than in other malignancies including breast and colorectal cancer, for which anti-HER2 agents are currently approved. Anti-HER2 antibody-drug conjugates are currently being tested in metastatic bladder cancer and may have utility in localized disease. The purpose of this study is to characterize patients with non-muscle invasive bladder cancer (NMIBC) harboring ERBB2 alterations that stand to benefit from the use of anti-HER2 targeted therapies.

Methods:

Patients diagnosed with NMIBC who underwent targeted exome sequencing with a 505 gene panel were identified (n=503). Patients with ERBB2 gene alterations were selected for analysis. Patients with multiple specimens (n=64) were excluded if discordance in ERBB2 alteration status was observed (n=6). Samples devoid of any mutation were also excluded to limit the effect of tumor impurity (n=2). Demographic and clinicopathologic measures were evaluated using descriptive statistics. Chi-squared analysis was used to compare differences in tumor stage, grade, and co-alteration frequency. The Benjamini-Hochberg procedure was used to estimate false discovery rate (q), and significant p-values were reported when q<0.05.

Results:

A total of 495 patients with NMIBC who underwent targeted exome sequencing of their tumors were included in the analysis. Median age was 67.9 years (IQR 60.6-75.1). ERBB2 alterations were observed in 85 patients (17%), most of which were missense mutations (11.9%) and amplifications (5.0%). Tumors with ERBB2 alterations were predominantly high-grade (96.6%) and invasive (58.0%). Over two-thirds (69.0%) of mutations were putative drivers, the most common of which was S310F (Figure 1). Compared to wild-type tumors, ERBB2-altered tumors were enriched in 50 distinct co-alterations. These included ERCC2 (35.1% vs. 10.3%, p<0.001), ARID1A (39.4% vs. 23.2%, p=0.001), RB1 (25.5% vs. 11.2%, p<0.001), E2F3 (20.1% vs. 5.1%, p<0.001), PPARG (18.3% vs. 6.7%, p<0.001), BRCA1 (13.8% vs. 3.7%, p<0.001), CHEK2 (11.7% vs. 3.2%, p=0.001), and MSH6 (9.6% vs. 1.3%, p<0.001). Notable differences were noted across homologous recombination repair genes (Figure 2). ERBB2 and FGFR3 alterations were mutually exclusive in the cohort. 

Conclusion:

Novel therapeutic strategies for NMIBC are urgently needed. ERBB2 alterations are frequently observed in high grade NMIBC and are associated with enrichment of oncogenic co-alterations, especially in homologous recombination repair genes. Preclinical studies and early phase clinical trials are warranted to study anti-HER2 small molecule inhibitors and antibody-drug conjugates in NMIBC.

Funding: Sidney Kimmel Center for Prostate and Urologic Cancers, NCI Cancer Center Core Grant Number P30-CA008748, NIH/NCI Grant Number R37CA276946, Cycle for Survival, Bladder Cancer Advocacy Network YIA, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, NCI T32 Award