Data from <i>ERBB2</i>/HER2 Alterations in ctDNA and Metachronous Tissues of Patients with Metastatic Urothelial Cancer

<div>AbstractPurpose:<p>HER2 targeting is increasingly relevant in metastatic urothelial cancer (mUC) because of emerging antibody–drug conjugates, in which assessment of tumor HER2/<i>ERBB2</i> status could aid interpretation of ongoing trials. We evaluated whether precise <i>ERBB2</i> genotype can be determined from mUC ctDNA and the relationship with tissue status.</p>Experimental Design:<p><i>ERBB2</i> genotype was determined through targeted sequencing of longitudinal samples from 226 patients with mUC. Heterogeneity was evaluated across ctDNA and metachronous tumor tissue <i>ERBB2</i> genotype and compared with HER2 IHC.</p>Results:<p>Activating <i>ERBB2</i> mutation and/or amplification was identified in 16% and 29% of patients by ctDNA and tissue sequencing, respectively. Alternatively, 55% of tissue samples were HER2 IHC positive. Agreement between HER2 IHC and <i>ERBB2</i> genotype (by either ctDNA or tissue) was 64%, in contrast to 87% between patient-matched ctDNA and tissue genotypes. Across serial samples, genotype and IHC revealed marked heterogeneity in <i>ERBB2</i> status. Factors linked with heterogeneity included <i>ERBB2</i> amplifications on extrachromosomal DNA, detected through whole-genome sequencing of ctDNA and FISH, and subclonal <i>ERBB2</i> mutations, which were evident in half of ctDNA and one-third of tissue samples.</p>Conclusions:<p>We report a combined analysis of HER2 IHC and <i>ERBB2</i> genotype in mUC ctDNA and archival tissue, revealing high spatiotemporal heterogeneity. Our data suggest that sole reliance on DNA- or protein-based HER2 assessment is insufficient to capture nuanced genomic indicators of HER2 pathway reliance and support a role for ctDNA alongside existing methods for characterizing HER2/<i>ERBB2</i> status during biomarker development in mUC.</p></div>