Validating the clinical utility of a novel prognostic biomarker and an oncogenic k-RAS signaling gatekeeper, SIAH, to risk stratify pancreatic cancer patients at Sentara-EVMS-VOA
Poster #: 097
Session/Time: B
Author:
Samantha Vos, BS
Mentor:
Amy H. Tang, PhD
Research Type: Clinical Research
Abstract
INTRODUCTION:
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer because it is often diagnosed at late stages where metastatic spread is common. Unlike other major cancer types, PDAC has an increased incidence rate, and is the 3rd leading cause of cancer death in the United States. Without early detection tools and curative regimens, PDAC is projected to become the 2nd leading cause of cancer death in 2030. Oncogenic K-RAS activation is a major driving force detected in >97% of PDAC cases, and is associated with rapid tumor relapse, chemo-resistance, metastasis, and dismal survival. KRAS is a small GTPase, and the oncogenic K-RAS pathway activation is multifaceted often rendering peotein inhibitors ineffective. SIAH is an evolutionarily conserved E3 ligase that is the most downstream signaling gatekeeper of the EGFR/K-RAS pathway whose function is indispensable in driving oncogenic K-RAS-driven PDAC malignancy. In this study, we aim to determine whether SIAH has prognostic value for patient risk stratification in the operable PDAC cohort to predict patient survival at Sentara. We predict that SIAHHigh expression may correlate with poor outcome and reduced survival in PDAC.
METHODS:
A cohort of 1,156 patients with PDAC, diagnosed at Sentara-EVMS-VOA between 2001-2016 was analyzed to determine the association of clinicopathological parameters with TNM staging, treatment efficacy, and survival prediction. SIAH expression was calculated by the average immunohistochemical (IHC) scores from two clinical pathologists in 148 operable PDAC patients, including 34 neoadjuvant chemotherapy (NACT)-treated residual tumors and 114 untreated primary tumors.
RESULTS:
354 PDAC patients were operable, and 802 patients were inoperable. 32.8% of the Caucasian patients and 27.4% of Black patients received surgical resection. Analysis of the SIAH expression in the 148 operable patients showed that low SIAH expression (< 5%) correlated with a longer survival than those with higher SIAH expression (>5%). The average SIAH expression in stage I/II and III/IV patients was recorded and SIAHhigh/low expression is correlated with the 1-2-3-4-5 years of survival post-diagnosis.
CONCLUSION:
We found that persistent SIAH expression in residual tumors post-NACT is indicative of chemo-resistant tumor cells at 1st-line setting, and thus representative of high-risk residual tumors associated with high rates of tumor relapse/chemo-resistance/systemic metastasis and the worst survival.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer because it is often diagnosed at late stages where metastatic spread is common. Unlike other major cancer types, PDAC has an increased incidence rate, and is the 3rd leading cause of cancer death in the United States. Without early detection tools and curative regimens, PDAC is projected to become the 2nd leading cause of cancer death in 2030. Oncogenic K-RAS activation is a major driving force detected in >97% of PDAC cases, and is associated with rapid tumor relapse, chemo-resistance, metastasis, and dismal survival. KRAS is a small GTPase, and the oncogenic K-RAS pathway activation is multifaceted often rendering peotein inhibitors ineffective. SIAH is an evolutionarily conserved E3 ligase that is the most downstream signaling gatekeeper of the EGFR/K-RAS pathway whose function is indispensable in driving oncogenic K-RAS-driven PDAC malignancy. In this study, we aim to determine whether SIAH has prognostic value for patient risk stratification in the operable PDAC cohort to predict patient survival at Sentara. We predict that SIAHHigh expression may correlate with poor outcome and reduced survival in PDAC.
METHODS:
A cohort of 1,156 patients with PDAC, diagnosed at Sentara-EVMS-VOA between 2001-2016 was analyzed to determine the association of clinicopathological parameters with TNM staging, treatment efficacy, and survival prediction. SIAH expression was calculated by the average immunohistochemical (IHC) scores from two clinical pathologists in 148 operable PDAC patients, including 34 neoadjuvant chemotherapy (NACT)-treated residual tumors and 114 untreated primary tumors.
RESULTS:
354 PDAC patients were operable, and 802 patients were inoperable. 32.8% of the Caucasian patients and 27.4% of Black patients received surgical resection. Analysis of the SIAH expression in the 148 operable patients showed that low SIAH expression (< 5%) correlated with a longer survival than those with higher SIAH expression (>5%). The average SIAH expression in stage I/II and III/IV patients was recorded and SIAHhigh/low expression is correlated with the 1-2-3-4-5 years of survival post-diagnosis.
CONCLUSION:
We found that persistent SIAH expression in residual tumors post-NACT is indicative of chemo-resistant tumor cells at 1st-line setting, and thus representative of high-risk residual tumors associated with high rates of tumor relapse/chemo-resistance/systemic metastasis and the worst survival.