This case in combination with the frequent discordance of ERBB2 status between primary and metastatic disease sites and tumor and cfDNA profiling suggests that archival tumor tissue should be used with caution for determining ERBB2 mutational and HER2 protein expression status in patients with metastatic urothelial cancer being considered for treatment with HER2-targeted ADCs and that HER2 mutational and expression heterogeneity is common in patients with urothelial cancer and may be a clinically relevant mechanism of T-DXd resistance. The gene discussed is ERBB2; the disease is neoplasm.