Endometrial Cancer by ERBB2 Amplification (ERBB2amp) Status: Differences in Molecular Subtypes, Ancestry, and Real-World Outcomes.

Abstract

Endometrial cancer (EC) has rising mortality rates and persistent racial disparities, particularly among non-Hispanic Black women who are more likely to present with aggressive histologic subtypes associated with worse survival. <i>ERBB2</i> amplification (<i>ERBB2</i>amp), a biomarker enriched in aggressive EC subtypes, is a therapeutic target. This study investigates <i>ERBB2</i>amp prevalence, molecular subtype, and histologic associations, as well as prognostic impact across diverse genetic ancestries using a large clinicogenomic database (CGDB). We analyzed 16,073 patients with EC who underwent tissue comprehensive genomic profiling via Foundation Medicine. Genetic ancestry was inferred using a single nucleotide polymorphism-based classifier. An outcomes cohort of 1,275 patients with advanced or recurrent EC from the Flatiron Health-Foundation Medicine CGDB was used to assess survival outcomes. Patients receiving human epidermal growth factor receptor 2 (HER2)-targeted therapy were excluded from the overall survival (OS) analysis. <i>ERBB2</i>amp prevalence, histologic and molecular correlations, and associations with OS were examined. <i>ERBB2</i>amp was identified in 8% of EC tumors, with the highest prevalence among patients of African ancestry (12% <i>v</i> 7% European ancestry; <i>P</i> < .001). There was a significant association between <i>ERBB2</i>amp and serous histology, <i>TP53</i> mutation presence, low tumor mutational burden, and microsatellite stability. In the outcomes cohort, <i>ERBB2</i>amp was not independently associated with OS (hazard ratio, 0.88 [95% CI, 0.65 to 1.17]; <i>P</i> = .37). In contrast, TP53mutation and poor performance status were independently associated with decreased OS. Notably, of patients with documented HER2 immunohistochemistry (IHC; n = 305), 22% of nonamplified tumors exhibited HER2 IHC 2+/3+ staining. <i>ERBB2</i>amp is more common among patients with African genetic ancestry and frequently co-occurs with <i>TP53</i>mutations, providing molecular rationale for EC disparities. Self-reported race does not fully capture genetic ancestry; therefore, comprehensive tumor profiling and HER2 IHC testing should be performed to improve selection for targeted therapies and help address disparities in EC outcomes.