Loss of SMAD4 Expression Associated with Worse Progression-Free and Overall Survival in Patients with Pancreatic Adenocarcinoma Treated Surgically

Abstract

The tumor suppressor gene SMAD4 is inactive in roughly half of patients with pancreatic adenocarcinoma. Several studies have linked los23s of SMAD4 with worse oncologic outcomes, while other studies have refuted this association. In this study, we examined the association of SMAD4 loss with oncologic outcomes in a cohort of patients with pancreatic adenocarcinoma treated with resection +/- adjuvant chemo-radiotherapy. Patients with non-metastatic adenocarcinoma of the pancreas s/p radical resection +/- adjuvant chemo-radiotherapy at the University of Pennsylvania were included. SMAD4 status was determined by immunolabeling assessment from the surgical pathology. Multiple assessments of SMAD4 status were obtained for each patient and the maximum, mean, and median value were analyzed. Kaplan-Meier survival analysis and Cox regression analysis was performed to assess the association of SMAD4 status with different oncologic outcomes of interest [(local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival, (OS)]. PFS was defined as time to first recurrence or death. P<0.05 was considered significant. 66 patients had evaluable SMAD4 tumor status and were included in the analysis. 59 received adjuvant chemo-radiotherapy; 7 received adjuvant chemotherapy alone. Median age was 65 (range 43 – 85). 35 patients were male (53%). Median follow-up was 23.5 months (range 3 – 141 months). 40 of 66 patients had complete loss of SMAD4 (61%). There were no significant differences in baseline demographic, clinical, pathologic, and treatment-related variables between the patients with intact vs. lost SMAD4 (p>0.05). On univariable Cox regression analysis, SMAD4 intact status was marginally associated with improved DMFS [HR 0.74 (95%CI 0.54-1.01), p=0.06) but was not predictive of LRFS [HR 0.96 (95%CI 0.67-1.39), p=0.85]. SMAD4 intact status was associated with significantly improved PFS [HR 0.72 (95%CI 0.54-0.95), p=0.02] and overall survival [HR 0.73 (95%CI 0.55-0.98), p=0.04). Median survival for patients with intact SMAD4 vs. SMAD4 loss was 37 months vs. 21 months (log-rank p=0.08). Results were similar when analyzed using median and mean SMAD4 values. For patients treated with surgical resection +/- adjuvant chemo-radiotherapy, loss of SMAD4 expression correlated with significantly worse progression-free survival and overall survival compared to patients with intact SMAD4. Loss of SMAD4 may help to predict patients at higher risk for recurrence following surgical resection and could help to guide future adjuvant therapy or help select patients for surgery or definitive radiotherapy.