Abstract
Background
Breast cancer is the 2nd leading cause of cancer death among women in the United States. Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. TNBC has 40-50% relapse and 22% survival rates. With extensive genetic diversity, tumor heterogeneity, and genomic instability, many similarly treated TNBC patients with identical clinicopathological characteristics (TNM/RCB) experience treatment disparity and disparate survival. Current methods fall short in predicting relapse/resistance/survival with high accuracy. Seven in Absentia Homologue (SIAH) is an evolutionarily highly conserved RING-domain E3 ligase that is the most downstream signaling gatekeeper of a major tumor-driving EGFR/RAS/RAF/MEK/ERK pathway, whose activation/inactivation was reflected in SIAHhigh/low expression. We propose that SIAH is a new prognostic biomarker for patient risk stratification and relapse/survival prediction in TNBC post-neoadjuvant chemotherapy (NACT).
Methods
A retrospective chart review was conducted using Sentara/EPIC and VOA iKnowMedicine portals to update clinical data in a large cohort of 553 TNBC patients. The IHC staining of SIAH, Ki67, EGFR, and H&E was performed in primary and residual tumors. Representative IHC images were captured. Statistical analyses, including Kaplan-Meier survival curves, were conducted to determine whether SIAHHigh/Low expression pre- and post-NACT, and NACT-induced reduction of SIAH expression in pair-matched TNBC tumor specimens is prognostic of relapse/chemoresistance/survival in high-risk TNBC.
Results
Among 553 TNBC patients, 180 high-risk patients received NACT. 51 of them have pair-matched primary and residual tumor biospecimens. 41 of them had Grade 3 tumors, and 21 of them had Stage II diseases. The statistical analyses demonstrated that high SIAH expression in residual tumors reflects persistent EGFR/K-RAS/SIAH pathway activation following ineffective NACT, predicting tumor relapse and poor survival. Conversely, no or low SIAH expression in residual tumors reflects EGFR/K-RAS/SIAH pathway shutdown by effective NACT, predicting tumor remission and improved survival. (p0.05)
Conclusion
High SIAH expression in residual tumors post-NACT was associated with TNBC malignancy and poor survival. We aim to develop a SIAH-centered biomarker panel to risk-stratify TNBC patients and predict relapse/resistance/survival at 1st-line neoadjuvant settings. This project aims to delineate the molecular underpinnings of the EGFR/RAS/SIAH pathway-driven treatment disparity and the persistently high mortality in TNBC in Virginia.