ERBB2 Alterations in Circulating Tumor DNA in Patients with Metastatic Urothelial Cancer - Expert Commentary
Activating ERBB2 mutations 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 ERBB2 genotype (by either ctDNA or tissue) was 64%, and 87% between patient-matched ctDNA and tissue genotypes. The study revealed marked heterogeneity in ERBB2 status across serial samples, with genotype and IHC showing substantial temporal variation. Factors linked with heterogeneity included ERBB2 amplifications on extrachromosomal DNA, detected through whole-genome sequencing of ctDNA and fluorescence in situ hybridization, and subclonal ERBB2 mutations, which were evident in half of ctDNA and one third of tissue samples.
Key findings demonstrated that only 50% of ERBB2 mutations showed clonal prevalence in ctDNA (cancer cell fraction 95% CI overlapping 1.0), indicating variability within metastatic tumor foci. ERBB2-altered patients exhibited significantly higher tumor mutational burden (median 18.0 versus 9.8 mutations per Mb, p=0.0003) but no difference in overall survival compared to wildtype cases. The study identified evidence for extrachromosomal DNA amplification in select cases through whole-genome sequencing, with AmpliconArchitect detecting ERBB2 ecDNA in two patients. The analysis revealed frequent intra-patient spatiotemporal heterogeneity, with 15% of ctDNA ERBB2 wildtype cases having alterations in tissue samples despite shared somatic mutations indicating common origin. HER2 IHC positivity (scores 2+/3+) was observed in 85% of tissue samples from ctDNA ERBB2-altered patients versus 45% of wildtype cases (p<0.00001). However, 46% of ERBB2 wildtype tissue samples were also HER2 IHC positive, indicating non-genetic mechanisms of protein expression.
This important analysis reveals high spatiotemporal heterogeneity in ERBB2/HER2 status that challenges single-analyte biomarker approaches. The data suggest that sole reliance on DNA or protein-based assessment inadequately captures HER2 pathway dependence, supporting integrated ctDNA and tissue evaluation for mUC biomarker development. The frequent subclonality and genomic instability associated with ERBB2 alterations may explain historical therapeutic failures and suggest that clonal alterations might better predict treatment response. Another important factor is the functional oncogenic addiction to ERBB2 signaling.
Written by: Bishoy M. Faltas, MD, Chief Research Officer, Englander Institute for Precision Medicine, Gellert Family - John P. Leonard, MD, Research Scholar, Associate Professor of Medicine, Cell and Developmental Biology, Weill Cornell Medicine, New York- Presbyterian Hospital, NY
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