Abstract C027: Persistent activation of this tumor-driving EGFR/RAS/RAF/MEK/MAPK/SIAH Pathway is highly prognostic in patient risk stratification, cancer disparity detection, and resistant/relapse/survival prediction at the 1st-line neoadjuvant settings
Authors: Tang Amy H. , Hoefer Richard A. , Guye Mary L. , Samli Billur , Winston Janet S. , Koblinski Jennifer , Robila Valentina , Idowu Michael O. , Jansen Rick J. , Bear Harry D. 
Published: December 2023

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. Neoadjuvant chemotherapy (NACT) is the standard-of-care (SOC) treatment for high-risk TNBC. With the approval of pembrolizumab, the addition of immune checkpoint blockade (ICB) to NACT has become the new SOC for high-risk early-stage TNBC. The pathologic complete response (pCR) is a reliable prognostic marker that indicates tumor remission and good prognosis, whereas pathologic incomplete response (pIR) with high residual cancer burden (RCB) is associated with early relapse, therapy-resistance, and reduced survival. However, clinical uncertainties remain, since many similarly-treated patients with identical TNM and RCB classifications often experience cancer disparity, health inequality, disparate outcome, and distinct survival. Current tools fall short in accurately detecting cancer disparity and forecasting tumor recurrence in real time.   We detected a major racial disparity in our large local cohorts of TNBC patients (&gt; 1,000 patients), of which 48% patients are Black/AA and 48% patients are white/Caucasian patients, at the Sentara Cancer Network and VCU Massey Cancer Center, that have provided excellent healthcare and quality cancer care to the social-economically-disadvantaged, medically underserved and underinsured racial/ethnic minorities, and historically Black/AA communities in Virginia. Despite the Sentara/VCU’s best effort, Black/AA cancer patients still suffer 70-100% higher cancer mortality, and the worst survival compared to their white counterparts, based on our clinical studies and the SEER/CDC databases. Supported by ample evidence in developmental, evolutionary, and cancer biology, we propose that persistent EGFR/RAS/SIAH pathway activation is a major driving force in breast cancer. The most downstream and evolutionarily conserved signaling gatekeeper, SIAH, is an RING domain E3 ligase that is a tumor-specific, therapy-responsive, and prognostic biomarker for patient risk stratification and cancer disparity prediction in breast cancer. High SIAH expression in residual tumors reflects ineffective treatment and tumor-driving EGFR/K-RAS/SIAH pathway activation (ON) that predict tumor relapse, treatment-resistance, poor outcome, and worst survival. Low SIAH expression in residual tumors reflects effective treatment and EGFR/K-RAS/SIAH pathway inactivation (OFF) that predicts tumor remission, treatment-sensitivity, and good outcome, and prolonged survival.  We found that SIAH expression is 2.0-fold higher in Black/AA residual tumors than of the white residual tumors, mirroring a 1.8-2.0-fold higher death rates reported in the Black/AA patients than their white counterparts. We aim to demonstrate the high precision and prognostic power of SIAH for relapse/resistance/survival prediction in NACT/NST-treated residual tumors in breast cancer.

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. Persistent activation of this tumor-driving EGFR/RAS/RAF/MEK/MAPK/SIAH Pathway is highly prognostic in patient risk stratification, cancer disparity detection, and resistant/relapse/survival prediction at the 1st-line neoadjuvant settings [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C027.