Abstract 3347: Developing a prognostic biomarker of EGFR/RAS/SIAH pathway activation/inactivation following neoadjuvant chemotherapy to risk stratify patients, detect racial disparity, and predict relapse and survival in triple-negative breast cancer

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young Black/white women. Hampton Roads, Virginia is a major cosmopolitan area with 1.8 million population, in which 30% are Black/African Americans. TNBC is highly prevalent in our area where high mortality and racial disparity are reported by CDC/SEERS databases. Supported by strong evidence in developmental, evolutionary, and cancer biology, we hypothesize that persistent EGFR/K-RAS/SIAH pathway activation is a major driving force of TNBC malignancy, and a new prognostic biomarker of racial disparity, early tumor relapse, and high mortality in the clinic. Methods: Chart review was conducted using Sentara MD Office/EPIC and VOA iKnowMedicine portals to update tumor relapse and survival of 535 TNBC patients. In a sub-cohort study, we focused on 183 high-risk TNBC patients who received neoadjuvant chemotherapy (NACT). We will determine if 5-year TNBC survival is associated with SIAHHigh/Low expression pre- and post-NACT, race, and/or other clinicopathological parameters. Results: We report that a higher SIAH expression in residual tumors post-NACT was associated with lower 5-year survival rates. In a cohort of 48 incomplete responders (pIR) post-NACT, the 5-year survival rate was 2.25-fold higher in patients whose residual tumors had a lower SIAH expression (< 50%) than those with a higher SIAH expression (> 50%) (61.5% vs 27.3%; p=0.02). Similarly, the 5-year survival rate was 3-fold higher in 18 pIR patients with stage 2 residual tumors that had a lower SIAH expression (<50%) than those with a higher SIAH expression (> 50%) post-NACT (100% vs 37.5%, p=0.01). A significant racial disparity in 5-year survival was detected between Black/white TNBC patients with stage 2 diseases post-NACT (95 vs 74%; p=0.005). Conclusion: A persistent high SIAH expression post-NACT was associated with reduced survival in high-risk TNBC patients. Encouraged by the preliminary data, we aim to develop a SIAH-centered biomarker panel, SIAHHigh (> 50%)/SIAHLow (<50%) by measuring the EGFR/K-RAS/SIAH pathway activation (ON)/inactivation (OFF) to risk stratify TNBC pIR patients, detect cancer racial disparities, forecast early tumor relapse, and predict survival at 1st-line neoadjuvant settings. We aim to delineate the molecular underpinning of the Black/white racial disparity in TNBC so that we can provide better, more equitable, and effective therapies to more high-risk TNBC patients with residual diseases in our local communities. Citation Format: Zachary Bouker, Amy H. Tang, Claire B. Piatak, Taylor N. Drake, Caroline D. Lee, Emily L. Breeding, Janet S. Winston, Billur Samli, Rick J. Jansen, Michael Danso, Richard A. Hoefer. Developing a prognostic biomarker of EGFR/RAS/SIAH pathway activation/inactivation following neoadjuvant chemotherapy to risk stratify patients, detect racial disparity, and predict relapse and survival in triple-negative breast cancer in Hampton Roads, Virginia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3347.