Abstract 7664: Early detection of 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/African American (AA) women. Black/AA patients have the highest mortality and the shortest survival of any racial/ethnic group in the US. With the approval of pembrolizumab, the addition of immune checkpoint blockade (ICB) to neoadjuvant chemotherapy (NACT) has become the standard of care (SOC) for high-risk early-stage TNBC. The pathologic complete response (pCR) is a reliable prognostic marker that correlates with tumor remission and good outcome, whereas pathologic incomplete response (pIR) with high residual cancer burden (RCB) is often associated with early relapse, treatment resistance, and poor survival. Many similarly-treated patients with identical TNM and RCB classifications still experience racial disparity, different relapse rates, and disparate survival. Current methods fall short in predicting tumor recurrence/chemo-resistance/patient survival with high accuracy in the clinic. Methods: We detected a major racial disparity in our large regional cohorts of TNBC patients (> 1,000 patients), of which 48% patients are Black/AA and 48% patients are white patients, at the Sentara Cancer Network and VCU Massey Comprehensive Cancer Center, that have historically provided excellent healthcare and quality cancer care to the social-economically-disadvantaged, medically underserved, and underinsured racial/ethnic minorities in low income communities in Virginia. Despite Sentara/VCU’s best efforts, Black/AA breast cancer patients still suffer 70-100% higher MBC mortality, and the worst survival compared to their white counterparts, based on our clinical studies and the SEER/CDC databases. Result: We showed that persistent EGFR/RAS/SIAH pathway activation is a major driving force of TNBC malignancy. The most downstream and evolutionarily conserved signaling gatekeeper, SIAH, is an RING domain E3 ligase that is a high-resolution prognostic biomarker for patient risk stratification and racial disparity prediction in TNBC. High SIAH expression in residual tumors reflects ineffective NACT/IO therapy and persistent EGFR/K-RAS/SIAH pathway activation (ON) that drives tumor relapse, resistance, and reduced survival. Low SIAH expression in residual tumors reflects effective NACT/IO therapy and EGFR/K-RAS/SIAH pathway inactivation (OFF) that predicts tumor remission, good outcome, and prolonged survival. We found that SIAH expression is 2.0-fold higher in Black/AA patients’ residual tumors than in the white patients’ residual tumors, mirroring a 1.8-2.0-fold higher death rates in the Black/AA patients than the white patients. Conclusion: In this study, we demonstrate the prognostic power of SIAH for patient risk stratification, therapy quantification, and relationship to cancer racial disparity 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 racial disparity and treatment resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7664.