Poorly differentiated histologic grade correlates with worse survival in SMAD4 negative pancreatic adenocarcinoma patients

Abstract

Background and ObjectivesThis study investigated the influence of the transcription factor SMAD4 on overall patient survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC).MethodsThe SMAD4 status of 125 surgically resected PDAC specimens at a large academic center from 2014 to 2017 was routinely determined prospectively and correlated with clinicopathologic characteristics and overall survival.ResultsSMAD4 loss was identified in 62% of patients and was not associated with overall survival (OS). On multivariate Cox proportional hazards survival analysis, histologic grade was the best predictor of survival in the SMAD4(−) population (adjusted hazard ratio = 4.8, p < .0001). In the SMAD4(+) population, histologic grade was not associated with survival on multivariate analysis. In the SMAD4(−) population, median OS for well/moderately differentiated patients and poorly differentiated patients was 39.6 and 8.6 months, respectively.ConclusionIn this large cohort of resected PDAC, routine SMAD4 assessment identified a subpopulation of patients with SMAD4(−) and histologically poorly differentiated tumors that had significantly poor prognosis with median OS of 8.6 months. Characterization of the role of SMAD4 within the context of poorly differentiated tumors may help settle the controversy regarding SMAD4 in PDAC and lead to identification of personalized therapeutic strategies for subgroups of PDAC.

The Role of SMAD4 Inactivation in Epithelial–Mesenchymal Plasticity of Pancreatic Ductal Adenocarcinoma: The Missing Link?

“…For example, in a study conducted by Yokose et al, SMAD4 alterations alone could not predict OS or DFS, but the combination of KRAS and SMAD4 mutations was an independent poor prognostic factor in PDAC [ 75 ]. In the same way, Park et al did not find any statistical difference in terms of OS in patients with SMAD4 loss, but poorly differentiated tumors that were SMAD4-negative were better predictors of survival [ 51 ].…”

“…In PDAC, a loss of SMAD4 expression has been associated with tumor size, peripancreatic extension, TNM staging, lymphatic invasion, nodal involvement and poor differentiation [ 51 , 52 , 53 ], influencing OS [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ] and DFS [ 56 , 59 , 61 , 64 ].…”