Abstract
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the United States. The current relative 5-year survival for PDAC is 8%, and the cause of this dismal prognosis is multifactorial, including often late-stage diagnosis and a multidrug-resistant nature. KRAS is a small GTPase and, when oncogenically hyperactivated, is involved in several signaling pathways indispensable for malignant transformation. In 2026, there are an estimated 67,530 new cases of PDAC, with KRAS mutations underpinning 90% of cases. SIAH is an evolutionarily conserved E3 ligase that is the most downstream signaling gatekeeper of the EGFR/KRAS signaling pathway identified thus far. In this clinical study, we aim to determine whether SIAH High/Low expression is a prognostic indicator of relapse and survival in the operable PDAC cohort at Sentara Hospitals.
Methods
This study’s cohort consists of 354 patients diagnosed with PDAC between 2001 and 2016 who underwent surgical resection at Sentara. 148 PDAC tumor specimens were stained for SIAH, Ki-67, and EGFR, including 116 untreated primary tumors and 31 neoadjuvant chemotherapy (NACT)-treated residual tumors. The biomarker expression was scored by two clinical pathologists to ensure IHC accuracy. Pathological TNM classifications were updated following the 8th edition AJCC guidelines. A combination of clinicopathological parameters and biomarkers was used to form groups for statistical analysis. Kaplan-Meier survival curves were generated to determine the prognostic value of SIAH High/Low in predicting overall survival (OS) and relapse-free survival (RFS) in PDAC.
Results
We observed increased survival in the borderline-operable cohort treated with NACT when compared to the upfront surgery primary cohort. Among the primary tumors, we found that high SIAH expression (>15%) is prognostic compared with patients with low SIAH expression (≤15%), in predicting decreased RFS in patients with stage III tumors (p0.03) and in patients with grade 2 tumors (p0.05).
Conclusion
We found that high versus low SIAH expression (15% cutoff) in the primary PDAC cohort is prognostic to predict patients’ RFS and OS while augmenting the standard clinicopathological parameters. Currently, there is no NCCN recommended pathological biomarker for risk stratification of PDAC tumors comparable to how the measurement of the protein Ki-67 is utilized in breast cancer. Given the limited efficacy of current treatment regimens in the recurrent and metastatic settings, and with the continued development of novel therapies, SIAH has potential as a prognostic biomarker to refine individual risk stratification and treatment planning. We hope that in the future, SIAH-guided risk stratification can inform treatment intensity, potentially reducing unnecessary exposure to chemotherapy and radiation while improving patient outcomes.