SMAD4 Loss: A predictor of worse tumor differentiation, early metastasis and shorter survival in pancreatic ductal adenocarcinoma

Abstract

Background: Among the various biomarkers available in pancreatic cancer, this study aimed to analyzes whether the expression patterns of SMAD4 are correlated with metastatic potential and are predictive of clinical outcome and survival in patients with pancreatic cancer. Methods: This is a prospective study conducted from March 2014 till February 2017, includes patients of pancreatic ductal adenocarcinoma who underwent surgical excision or tru-cut biopsy. Results: Among forty-five patients, 33 had loss while 12 had intact SMAD4. Loss of SMAD4 carries a 1.3 times increased risk of vascular and 1.6 times risk of nodal spread. Deletion of SMAD4 was associated with poor differentiation (p=0.04,OR=5.6,C.I=0.9-34.4), and increased the risk of perineural invasion by two times (OR=2,C.I=0.1-34.8). Thirty-three, eighteen, and five patients survived at the end of 6, 12 and 24 months respectively. Analysis revealed statistically significant association between SMAD4 loss and survival at six months (p=0.04), 12 months (p=0.01) and 24 months (p=0.007). Among the operated patients (n=19), eleven patients developed recurrence during follow-up, period. all had loss of SMAD4 (p=0.03). The hazard ratios for poor tumor differentiation and SMAD4 loss were 5.8 (95%C.I=1.2-28.4,p=0.02) and 6.7 (HR=6.7,95%C.I=1.9-23.3,p=0.002) respectively. The SMAD4 intact and loss group had median survival of 19.5+2.1 months (95%C.I=15.4-23.7) and 9.3+1.0 months (95%C.I=7.3-11.4) respectively, confers a survival advantage of 10 months (p=0.002,C.I.=-4.1to-0.9). Conclusion: Loss of SMAD4 is strongly associated with poor tumor differentiation with risk of metastasis at presentation. The overall survival is significantly influenced by the loss of SMAD4 and poor tumor differentiation.