Presentations

Abstract

Introduction:

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in American women. A major unmet clinical need is that Black/African American (AA) women still suffer the highest mortality from breast cancer than any other race or ethnic group in the United States, despite the breakthrough therapy and technology advancement in the last 20 years. Triple-negative breast cancer (TNBC), characterized by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive molecular subtype in breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S. and is known for high relapse rates and poor overall survival (OS). TNBC is nearly twice as common in Black/AA women than in white women. In this study, we aim to risk stratify patients, detect cancer racial disparity, and predict relapse/survival in the clinic, especially among Black/white TNBC patients by comparing their length of disease, age at diagnosis, time between initial diagnosis and treatment given, neoadjuvant response, insurance status, and overall survival at Sentara and VCU.

In this study, we have focused on Seven-in-Absentia Homolog (SIAH), an evolutionary conserved RING-domain E3 ubiquitin ligase that is the most downstream signaling gatekeeper of EGFR/K-RAS signaling pathway. We report that the constitutive activation of the oncogenic EGFR/RAS/SIAH pathway is a major driving force in early tumor relapse, chemo- resistance, and systemic metastasis in human cancers. Our published studies have shown that SIAH expression is highly prognostic in high-risk and locally advanced breast cancer. We reported that SIAH's prognostic value was far superior to these commonly used clinical biomarkers, such as ER, PR, HER2, and Ki67. Importantly, SIAH's prognostic accuracy alone was comparable to the clinical gold standard, i.e., lymph node metastasis, mammary tumor size grade, stage, and molecular subtypes, in NACT/NST-treated breast cancer. We predict that SIAH can be used to further risk stratify patients and predict patient survival in 1st-line neoadjuvant settings. Furthermore, we will determine the clinical utility of SIAH to predict relapse/outcome/survival and detect cancer racial disparity. We predict SIAH expression would be higher in the Black/AA tumors than that of the white/Caucasian tumors by population average.

Methods:

Clinicopathological parameters and survival data were extracted and confirmed at Sentara MD Office and EPIC, de-identified clinical databases were established, and standard treatment regimens were extracted. We have and will conduct statistical analysis on the NACT/NST-treated breast cancer cohort and TNBC patient cohorts of the two major race groups by conducting Kaplan Meier survival curves, COX proportional hazards regression test, ANOVA, Chi Square and/or Fischer's Exact test, and student t-test. In doing so, we aim to delineate the impact of multifactorial contributors, such as age at diagnosis, length of disease, time between initial diagnosis and treatment given, neoadjuvant response, insurance status, and overall survival as well as SIAHHigh/Low expression in residual tumors for patient risk stratification and survival prediction.

Results:

At Sentara and VCU, we found that the time lapse between initial diagnosis and 1st treatment administered is significantly longer in Black/AA when compared to their white counterparts. There is similar insurance coverage across both racial groups in our two cohorts. In both cohorts, the average SIAH expression levels seemed to be higher in the Black/AA tumors than that of the white tumors. The SIAH IHC data are incomplete, and the study is still ongoing. Lastly, SIAH has shown clear statistical significance to risk stratify partial responders with residual diseases to predict relapse/survival in two major racial groups at Sentara and VCU.

Conclusion:

It is important to identify the determinacy of cancer racial disparity, especially in Hampton Roads Virginia and Richmond Virginia, in which breast cancer mortality in our Black/AA patients is 1.7-2.0-fold higher than that of the national average, i.e., a glaring 1.4-fold higher breast cancer mortality rate in Black/AA patients than their white counterparts in the US. We aim to implement the NCCN standard of care and promote treatment adherence, as well as deploy SIAH as a new and precision prognostic biomarker to risk stratify, detect cancer racial disparity, and improve the overall survival of patients diagnosed with high-risk breast cancer, especially Black/AA patients in Virginia.