Validating the prognostic utility of SIAHHigh/Low protein expression as a downstream readout of TNBC-driven EGFR/RAS pathway activation (ON)/inactivation (OFF) to risk stratify TNBC patients in the clinic
Poster #: 100
Session/Time: A
Author:
Mark Matta, MS
Mentor:
Amy H. Tang, PhD
Research Type: Clinical Research
Abstract
INTRODUCTION:
Breast cancer is the 2nd leading cause of cancer death in women in the United States. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young women. TNBC represents ~ 15-20% of all breast cancers. TNBC has high relapse rates and poor survival. With high genetic diversity, dynamic tumor heterogeneity, and genomic instability, many similarly treated TNBC patients with identical clinicopathological characteristics experience treatment disparity and disparate survival. Current methods fall short in predicting relapse/resistance/survival with reliable accuracy. Seven in absentia homologue (SIAH) is an evolutionarily highly conserved RING-domain E3 ligase that is the most downstream signaling gatekeeper identified in the EGFR/HER2/K-RAS/RAF/MEK/MAPK signaling pathway. We propose that SIAH is a new prognostic biomarker for patient risk stratification and relapse/survival prediction in TNBC post-neoadjuvant chemotherapy (NACT).
METHODS:
Chart review was conducted using Sentara MD Office/EPIC and VOA iKnowMedicine portals to update patient survival in a large cohort of 577 TNBC patients. The IHC staining of SIAH, Ki67, and EGFR were performed in TNBC primary and residual tumors. Representative IHC images were captured. Statistical analyses were conducted to determine whether SIAHHigh/Low expression pre- and post-NACT, and the NACT-induced changes of SIAH High/Low expression in the pair-matched TNBC tumor specimens can be used to predict relapse/resistance/survival in high-risk TNBC.
RESULTS:
Among 577 TNBC patients, 317 high-risk patients received NACT. 75 of them are pCR patients and 233 are pIR patients. 133 of them have both the primary and residual tumor biospecimens. The KM survival curves were performed. We found that high SIAH expression in residual tumors reflects ineffective NACT and persistent EGFR/K-RAS/SIAH pathway activation that predict high relapse, chemo-resistance, and poor survival. Conversely, low SIAH expression in residual tumors post NACT, reflects effective EGFR/K-RAS/SIAH pathway inactivation that predict tumor remission and improved survival.
CONCLUSION:
High SIAH expression in TNBC residual tumors post-NACT was associated with high-risk TNBC malignancy. We aim to develop a SIAH-centered biomarker panel to risk stratify TNBC pIR patients and predict relapse/resistance/survival at 1st-line neoadjuvant settings. We aim to delineate the molecular underpinning of the EGFR/RAS/SIAH-driven treatment disparity in TNBC in Virginia.
Breast cancer is the 2nd leading cause of cancer death in women in the United States. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young women. TNBC represents ~ 15-20% of all breast cancers. TNBC has high relapse rates and poor survival. With high genetic diversity, dynamic tumor heterogeneity, and genomic instability, many similarly treated TNBC patients with identical clinicopathological characteristics experience treatment disparity and disparate survival. Current methods fall short in predicting relapse/resistance/survival with reliable accuracy. Seven in absentia homologue (SIAH) is an evolutionarily highly conserved RING-domain E3 ligase that is the most downstream signaling gatekeeper identified in the EGFR/HER2/K-RAS/RAF/MEK/MAPK signaling pathway. We propose that SIAH is a new prognostic biomarker for patient risk stratification and relapse/survival prediction in TNBC post-neoadjuvant chemotherapy (NACT).
METHODS:
Chart review was conducted using Sentara MD Office/EPIC and VOA iKnowMedicine portals to update patient survival in a large cohort of 577 TNBC patients. The IHC staining of SIAH, Ki67, and EGFR were performed in TNBC primary and residual tumors. Representative IHC images were captured. Statistical analyses were conducted to determine whether SIAHHigh/Low expression pre- and post-NACT, and the NACT-induced changes of SIAH High/Low expression in the pair-matched TNBC tumor specimens can be used to predict relapse/resistance/survival in high-risk TNBC.
RESULTS:
Among 577 TNBC patients, 317 high-risk patients received NACT. 75 of them are pCR patients and 233 are pIR patients. 133 of them have both the primary and residual tumor biospecimens. The KM survival curves were performed. We found that high SIAH expression in residual tumors reflects ineffective NACT and persistent EGFR/K-RAS/SIAH pathway activation that predict high relapse, chemo-resistance, and poor survival. Conversely, low SIAH expression in residual tumors post NACT, reflects effective EGFR/K-RAS/SIAH pathway inactivation that predict tumor remission and improved survival.
CONCLUSION:
High SIAH expression in TNBC residual tumors post-NACT was associated with high-risk TNBC malignancy. We aim to develop a SIAH-centered biomarker panel to risk stratify TNBC pIR patients and predict relapse/resistance/survival at 1st-line neoadjuvant settings. We aim to delineate the molecular underpinning of the EGFR/RAS/SIAH-driven treatment disparity in TNBC in Virginia.