Abstract 5531: Early detection of cancer disparity and treatment resistance in TNBC

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and disproportionately affects BRCA1 mutation carriers and young black women. Black/African American (AA) patients with TNBC have the highest mortality rate and the shortest survival of any racial/ethnic group in the United States. TNBC challenges our ability to personalize effective therapy. Neoadjuvant chemotherapy (NACT) is the standard-of-care (SOC) to treat T2 or LN+ TNBC. The addition of immune checkpoint blockade (ICB) has revolutionized treatment for these high-risk patients. Pembrolizumab plus chemotherapy is the new SOC for neoadjuvant systemic therapy (NST) in TNBC. Pathologic complete response (pCR) is a reliable indicator that correlates with improved long-term survival. However, clinical uncertainties remain in those who have an incomplete pathologic response (pIR) since many similarly treated TNBC patients with identical stage and comparable residual cancer burden (RCB) demonstrate disparate clinical outcomes. Current methods fall short in predicting tumor recurrence and treatment resistance in the clinic. Supported by ample evidence in developmental, evolutionary, and cancer biology, we proposed that EGFR-K-RAS-SIAH pathway activation is a major driving force in TNBC and that its most downstream gatekeeper, SIAH, is a tumor-specific, therapy-responsive, and prognostic biomarker for patient risk stratification in TNBC. The persistent high expression of SIAH in residual tumors after neoadjuvant therapy reflects EGFR/K-RAS pathway activation (ON) and resistance to treatment. The loss of expression of SIAH in residual tumors reflects EGFR/K-RAS pathway inactivation (OFF) and response to treatment (i.e. treatment efficacy). Here we propose to establish the power of SIAH as a prognostic biomarker to differentiate high-risk from low-risk tumors and predict “real-time” therapy response, in both pre- and post-neoadjuvant (NACT/NST) setting. Breast cancer mortality rates in Hampton Roads Virginia and Richmond Virginia are among the worst in the U.S. and demonstrate a major cancer health disparity. Black patients in our region have a 60-70% higher mortality rate than white patients according to CDC/SEER databases. Using a large cohort of 525 racially diverse TNBC patients (246 black and 279 white patients) at Sentara Cancer Network, we conducted Kaplan-Meier survival analyses and detected a major racial disparity, with significantly lower survival among the Black/AA TNBC cohort, compared to national databases. We will expand this TNBC disparity study by using 2 large racially-diverse cohorts of 981 TNBC patients (459 Black and 493 white patients) from the Sentara Cancer Network and VCU Massey Cancer Center to analyze the prognosis of SIAH expression. By focusing on this tumor-driving EGFR-K-RAS-SIAH pathway, we aim to delineate the underlying molecular basis of treatment resistance and racial disparity in high-risk TNBC. Citation Format: Amy H. Tang, Richard A. Hoefer, Dasom Lee, Emily L. Breeding, Mary L. Guye, Janet S. Winston, Billur Samli, Jennifer Koblinski, Valentina Robila, Michael O. Idowu, Rick J. Jansen, Harry D. Bear. Early detection of cancer disparity and treatment resistance in TNBC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5531.