PS4-05-23: Investigating Interferon Pathway Biomarkers as Predictors of Disease Free Survival in Triple Negative Breast Cancer

Abstract Background: Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers, characterized by aggressive clinicopathology, limited targeted therapies, and high rates of early recurrence. Immune activation, particularly type I interferon (IFN) signaling, has emerged as a key modulator of tumor behavior, response to therapy, and patient outcomes in TNBC. However, the impact of IFN pathway regulators on long-term prognosis remains unclear. As modulators of immune activation, ADAR1 and ISG15 are IFN pathway genes that may influence the tumor-immune microenvironment and clinical outcomes in TNBC. This study investigates whether ADAR1 and ISG15 expression are associated with disease-free survival in TNBC, aiming to clarify their prognostic significance and potential interplay as immune-modulatory biomarkers in this high-risk breast cancer subtype. We hypothesized that the expression of ADAR1 and ISG15 would be linked to DFS events. Methods: This cohort was prepared by the St. Louis Breast Tissue Registry, derived from tissue microarrays (TMAs) constructed from surgical tumor blocks of 326 patients with TNBC diagnosed between 1973 and 2022 who underwent curative surgery as the immediate therapy at the Barnes-Jewish Hospital and Siteman Cancer Center. All clinical data and tissue specimens were collected by the Washington University Institutional Review Board (IRB #201102394). Information was deidentified prior to distribution of TMA to investigators. For this study, disease-free survival (DFS) is defined as the time from diagnosis to recurrence, second primary malignancy, death or last disease-free follow-up. ISG15 and ADAR1 expression were examined by immunohistochemistry and scored by Allred and HALO. Clinical and pathological data were systematically annotated and analyzed using custom R scripts. Descriptive statistics were employed to summarize clinical and molecular variables. Cox proportional hazards models were generated to assess the association of biomarker expression with DFS. Kaplan-Meier survival analysis was used to evaluate clinical outcome and additional models were constructed to explore the impact of clinical stage and race on DFS. Results: The median age was 56.5 years, with 225 White and 101 Black patients. 221 patients were disease-free at follow-up. Median follow-up time was 10 years. In this cohort, stage was prognostic for DFS in multivariate analysis. Cytoplasmic ADAR1 and ISG15 expression were significantly higher in Black patients compared to White patients (6.49 vs. 5.95, 0.92 vs. 0.84, p = 0.044, 0.041). However, race was not independently predictive of disease-free survival in this model (p = 0.80). Higher ISG15 expression was associated with improved DFS through univariate analysis (p = 0.03) but not in multivariate analysis that included stage. Interestingly, patients who were disease-free at follow-up had significantly higher ADAR1 expression through univariate analysis (mean difference = 0.571, 95% CI: [-1.09, -0.05], p = 0.030). Kaplan-Meier analysis confirmed that high expression was correlated with DFS (p = 0.012). However, in this cohort, patients with higher ADAR1 expression also have a higher rate of adjuvant chemotherapy (p=0.01) and those treated with chemotherapy are more likely to be disease-free than patients who did not undergo chemotherapy (p=0.012). Conclusion: To our knowledge, this study is the first to examine the association between IFN pathway regulators, ISG15 and ADAR1, and TNBC prognosis. The finding of increased ISG15 in association with improved DFS is consistent with the likely activated IFN pathway state for these tumors. Additional analysis is ongoing to examine the association of these markers with immune cell infiltration and the expression of immune checkpoints. Citation Format: K. Yuan, S. Humble, A. Mabry, R. Kladney, L. Maggi, C. X. Ma, J. D. Weber, G. A. Colditz. Investigating Interferon Pathway Biomarkers as Predictors of Disease Free Survival in Triple Negative 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 PS4-05-23.