Loss of HES-1 Expression Predicts a Poor Prognosis for Small Intestinal Adenocarcinoma Patients

Objective: Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to KRAS mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well-understood. Materials and Methods: To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and KRAS genotype, in 185 small intestinal adenocarcinomas. Results: The loss of HES-1 expression (HES-1^Loss) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (P = 0.018), pancreatic invasion (P = 0.005), high grade (P = 0.043), and non-tubular histology (P = 0.004). Specifically, in tumors with mutant KRAS (KRAS ^MT), HES-1^Loss was related to proximal location (P = 0.024), high T and N categories (P = 0.005 and 0.047, respectively), and pancreatic invasion (P = 0.004). Patients with HES-1^Loss showed worse overall survival compared to those with intact HES-1 (HES-1^Intact) (P = 0.013). Patients with HES-1^Loss/KRAS ^MT (median, 17.3 months) had significantly worse outcomes than those with HES-1^Intact/KRAS ^WT (39.9 months), HES-1^Intact/KRAS ^MT (47.6 month), and HES-1^Loss/KRAS ^WT (36.2 months; P = 0.010). By multivariate analysis, HES-1^Loss (hazard ratio = 1.55, 95% confidence interval (CI), 1.07-2.26; P = 0.022) remained an independent prognostic factor. Conclusion: HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.