Abstract PS3-11-24: The Combined Immune-Stromal Score (CISS): A Novel Prognostic Gene Signature in Early both ER-positive and HER2-positive Breast Cancer

Abstract Background: Despite therapeutic advances, patients with both estrogen receptor (ER)-positive and Human Epidermal growth factor Receptor 2 (HER2)-positive breast cancers have persistent clinical heterogeneity. We hypothesized that stromal-immune interactions within the tumor microenvironment (TME) drive differential treatment outcomes. Materials and methods: We analyzed 356 primary surgical HER2-positive tumors (treated with adjuvant trastuzumab) using gene expression panel profiling derived from formalin-fixed paraffin-embedded (FFPE) specimens. Unsupervised clustering of pathway enrichment levels was performed. The Combined Immune-Stromal Score (CISS) was developed, and we validated it for associations with recurrence-free survival (RFS) in both ER-positive and HER2-positive patients. Validation was performed using independent validation cohorts: PREDIX HER2 (neoadjuvant), SCAN-B, METABRIC, and TCGA. Results: Four biological subgroups were identified, characterized by differences in stromal markers (stromal), immune infiltration, cytokine and chemokine signaling, and antigen presentation (immune). Patients with Low_stromal and Low_immune tumors had significantly worse RFS compared to Low_stromal and High_immune (adjusted Hazard Ratio (HRadj) = 2.55, 95% confidence interval (CI) = 1.09-5.95, p = 0.03), and High_stromal and Low_immune (HRadj = 2.30, 95% CI = 1.18-4.48, p = 0.01). In both ER-positive and HER2-positive patients, each unit increase in CISS was associated with a 40% reduction in recurrence risk (HRadj = 0.60, 95% CI = 0.42-0.86, p = 0.00544), a finding consistently replicated across validation cohorts. Patients with low-CISS tumors (concurrent low stromal and low immune activity) demonstrated a worse prognosis (Log Rank p = 0.0069). Conclusions: The Combined Immune-Stromal Score (CISS) is a novel gene expression-based signature that stratifies recurrence risk in early both ER-positive and HER2-positive breast cancer. Tumors with low CISS, characterized by concurrently low stromal and immune pathway activity, were associated with significantly poorer outcomes. These findings suggest that a suppressed TME may contribute to recurrence risk and highlight the potential of CISS as a prognostic tool and a basis for future studies exploring therapeutic vulnerabilities. Citation Format: q. yang, C. Rönnlund, C. Schagerholm Stanev, X. Chen, T. Foukakis, K. Wang, I. Fredriksson, R. Stephanie, E. G. Sifakis, J. Hartman. The Combined Immune-Stromal Score (CISS): A Novel Prognostic Gene Signature in Early both ER-positive and HER2-positive Breast Cancer [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 PS3-11-24.