Presentations

Abstract

Introduction: The incidence and numbers of the death due to pancreatic cancer have doubled from 1990-2017. Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and deadliest form of human cancer that lacks early detection tools and curative treatment regimens in the clinic. Oncogenic K-RAS mutation is universally activated in PDAC tumors, that drive tumor progression, invasion, early relapse, chemo-resistance, and dismal survival. In this study, we focus on the oncogenic K-RAS signaling pathway to examine whether SIAH, an evolutionarily conserved E3 ligase that is the most downstream signaling gatekeeper of the EGFR/K-RAS pathway, has prognostic value 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 are operable, and 802 patients are inoperable. 32.8% of the white/Caucasian patients and 27.4% of Black/AA patients received surgical resection. A comparison of the 5-year survival rate between the locally treated cohort and the national average from 2001 to 2016 shows underperforming local survival rates that start to approach national standards after 2010. Analysis of the SIAH expression in 34 NACT-treated residual tumors showed that low SIAH expression (< 5%) correlated with a longer survival than those with higher SIAH expression (>5%).

Conclusion: A 5.4% difference between the two-race groups in the operable cohort may indicate that Black patients are more likely to present with advanced, unresectable PDAC. The gap between local and national 5-year survival rates starts to narrow after 2010, which reflects a better understanding and timely implementation of more effective treatment modalities of PDAC, including the Whipple procedure, and NACT regimens for all the eligible operable PDAC patients at Sentara-VOA. We reported 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 that is prone to develop early relapse and poor survival.