Presentations

Abstract

Introduction: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young Black/white women. 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, racial disparity, early relapse, and high mortality.

Methods: Chart review was conducted using Sentara MD Office/EPIC and VOA iKnowMedicine portals to update tumor relapse, metastasis, and survival in 535 TNBC patients. In this study, we focused on 183 patients who received neoadjuvant chemotherapy (NACT). 5-year survival and pre- and post-NACT SIAH expression were analyzed to determine if survival is associated with SIAH expression, race, and/or other clinicopathological parameters.

Results: We found 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 approximately 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 approximately 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 was also found for 5-year survival between stage 2 white and black NACT-TNBC patients (95 vs 74%; p=0.005).

Conclusion: A persistent high SIAH expression was associated with reduced survival in high-risk TNBC patients post-NACT. A striking racial disparity in 5-year survival was also detected in Stage 2 TNBC patients who were treated with neoadjuvant therapy. Encouraged by our 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 pIR patients, detect cancer racial disparities, forecast tumor relapse, and predict survival at 1st-line neoadjuvant settings. We also aim to delineate the molecular underpinning of the Black/white racial disparity in TNBC so that we can provide better, more equitable, high-quality, and precision care to our local community.