Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p<0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p<0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]