Abstract 3336: Early detection of tumor relapse, racial disparity, and treatment resistance in triple negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young Black/white women. Black/AA patients have the highest mortality and the shortest survival of any racial/ethnic group in the US. Pembrolizumab and neoadjuvant chemotherapy (NACT) has become the standard of care (SOC) for high-risk early-stage TNBC. Pathologic complete response (pCR) predicts good outcome, whereas pathologic incomplete response (pIR) with high residual cancer burden (RCB) is correlated with early tumor relapse, treatment resistance, and poor survival. Many similarly treated patients with identical TNM and RCB classifications experience treatment disparity, distinct relapse rates, and disparate survival. Current methods fall short in predicting early tumor relapse/chemo-resistance/patient survival with high accuracy in the clinic. Methods: We have conducted IHC staining of EGFR, Ki67, SIAH and PD-L1 expression in a large cohort of TNBC patients (> 1,000 patients), of which 48% patients are Black/AA and 48% patients are white patients, from the Sentara Cancer Network and VCU Massey Comprehensive Cancer Center, both of which serve socio-economically-disadvantaged, medically underserved, and underinsured racial/ethnic minorities in low-income communities in Virginia. Results: We found that high SIAH expression in residual tumors reflects ineffective therapy and persistent EGFR/K-RAS/SIAH pathway activation (ON) and predicts early relapse, chemo-resistance, and poor survival. Conversely, low SIAH expression in residual tumors reflects effective therapy and EGFR/K-RAS/SIAH pathway inactivation (OFF) and predicts tumor remission and good survival. We detected a major racial disparity in the large TNBC cohort. Black/AA breast cancer patients suffer a higher MBC mortality and reduced survival compared to their white counterparts in our clinical studies similar to the SEER/CDC databases. Conclusions: We found that persistent EGFR/RAS/SIAH pathway activation is a major driving force in TNBC malignancy. As an evolutionarily conserved RING-domain E3 ligase, SIAH is a new prognostic biomarker for patient risk stratification, tumor relapse prediction, and racial disparity detection in TNBC. We aim to validate the prognostic power of SIAH and develop a SIAH-centered biomarker panel for patient risk stratification and relapse/resistance/survival prediction in TNBC. Citation Format: Amy H. Tang, Richard A. Hoefer, Mary L. Guye, Billur Samli, Janet S. Winston, Jennifer Koblinski, Valentina Robila, Michael O. Idowu, Rick J. Jansen, Harry D. Bear. Early detection of tumor relapse, racial disparity, and treatment resistance in triple negative breast cancer [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 3336.