EGFR/RAS/SIAH pathway-centered biomarker-based prediction of tumor relapse/chemo-resistance/patient survival in TNBC

Introduction: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young Black/white women. Pembrolizumab and neoadjuvant chemotherapy (NACT) has become the new standard of care (SOC) for high-risk early-stage TNBC. Pathologic complete response (pCR) predicts good outcome, whereas pathologic incomplete response (pIR) with high-risk residual cancer burden (RCB) is correlated with early tumor relapse, chemo-IO-resistance, and poor survival. Many similarly treated patients with identical TNM and RCB classifications experience clear treatment disparity, distinct relapse rates, and disparate survival. Current methods fall short in predicting relapse/resistance/survival with high precision in the clinic. Methods: We have conducted IHC staining of EGFR, Ki67, and SIAH expression in a large cohort of TNBC patients (577), of which 48% patients are Black/AA and 48% patients are white patients, from the Sentara Cancer Network. The Sentara Comprehensive Breast Centers have served our military veterans (Naval Norfolk Station) as well as many socio-economically disadvantaged, medically underserved, and underinsured low-income patients from Hampton Roads Virginia, with a racially diverse population of 1.8 million. Results: We reported that high SIAH expression in residual tumors post-NACT reflects persistent EGFR/K-RAS/SIAH pathway activation (ON), predicts ineffective SOC therapy, continuous tumor growth post-NACT, which predicts early relapse, chemo-resistance, and poor survival. Conversely, no or super-low SIAH expression in residual tumors post-NACT reflects effective SOC therapy, EGFR/K-RAS/SIAH pathway inactivation (OFF), which predicts tumor remission and prolonged survival. We found that our Black/AA TNBC patients suffer a significantly higher mortality and reduced survival when compared to their white counterparts in this study, 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. SIAH is a major tumor vulnerability in TNBC malignancy. We aim to demonstrate the prognostic power of SIAH and develop a SIAH-centered biomarker panel for patient risk stratification and relapse/resistance/survival prediction in high-risk TNBC.