Abstract PS3-10-24: Biologic and Pathologic Correlations of the HER2DX Genomic Test in HER2+ Disease

Abstract HER2DX is a genomic test developed to guide treatment decisions in newly diagnosed HER2-positive (HER2+) breast cancer. It analyzes the expression of 27 genes grouped into 4 biological signatures: immune/immunoglobulin (IGG), luminal differentiation, proliferation, and HER2 amplicon expression. The test provides three distinct outputs: a prognostic relapse risk score, a pathologic complete response (pCR) likelihood score, and a quantitative ERBB2 mRNA score. This study investigates the relationship between HER2DX-derived outputs and standard histopathologic features in early-stage HER2+ breast cancer. The standardized HER2DX genomic test provided by Reveal Genomics was performed on paraffin tumor samples from newly diagnosed patients with early-stage HER2+ breast cancer, treated across 24 hospitals from January 2022 to June 2025. Histopathologic evaluation of hematoxylin-eosin-stained slides included tumor grade, stromal tumor-infiltrating lymphocytes (TILs) percentage, spatial TIL distribution, and presence of tertiary lymphoid structures (TLS). Hormone receptor (HR) status and Ki67 proliferative index were assessed locally by immunohistochemistry (IHC), while HER2 status was determined using IHC and in situ hybridization. Associations between HER2DX scores and pathologic features were assessed using appropriate statistical tests for continuous variables and categorical comparisons. HER2DX scores and their underlying biological signatures were analyzed in 410 HER2+ tumors. HR+ disease represented 75.7% of cases. The distribution of tumor grade, HER2 IHC status, HR status, Ki67 index, stromal TILs, TLS, and TIL spatial patterns is summarized in the Table. The HER2DX pCR score was significantly associated with all histopathologic features evaluated, the relapse-risk score five of these features (including Ki67 and TILs), and the HER2DX ERBB2 score with HER2 and HR status. Higher stromal TIL levels were moderately correlated with the IGG signature (r=0.59, p<0.001), and the inflamed TIL distribution was associated with increased IGG signature expression and higher HER2DX pCR scores (p<0.001). TLS presence also correlated with elevated IGG signature expression (p<0.001). HR+ tumors exhibited higher luminal signature expression (p<0.001), while HER2 IHC 3+ tumors had increased HER2 amplicon signature and HER2DX ERBB2 scores (p<0.001). Finally, higher Ki67 levels were moderately correlated with the proliferation signature (r=0.50, p<0.001). The HER2DX genomic test shows significant associations with multiple histopathologic features in early-stage HER2+ breast cancer, although no single feature can fully explain the outputs of the test. These findings support the notion that HER2DX integrates complex biological and histological dimensions, offering complementary information that may enhance personalized treatment decision-making. Citation Format: E. Sanfeliu, A. Martinez-Romero, M. Marín-Aguilera, S. Cobo, B. González-Farré, E. Hernandez, P. Jares, J. Puig-Butillé, M. Muñoz, R. Gómez-Bravo, M. Tapia, C. Tebar, C. Saura, S. Escrivà-de-Romaní, J. Soberino, J. Cortés, S. Morales, K. Amillano, L. Paré, P. Villagrasa, W. Buckingham, F. Pardo, J. Parker, F. Brasó-Maristany, E. Ciruelos, R. Sánchez-Bayona, O. Martinez-Sáez, J. Cejalvo, A. Prat. Biologic and Pathologic Correlations of the HER2DX Genomic Test in HER2+ Disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-10-24.