SMAD4 as a Predictive Biomarker For Locally Aggressive Phenotype In Resected Pancreas Cancer

Abstract

The primary challenge in management of operable pancreas cancer is identifying patients in which aggressive local therapies is warranted to increase survival. Previous reports indicate intact SMAD4, a tumor suppressor gene inactivated in the majority of pancreas cancer, is associated with a locally aggressive phenotype. We sought to determine the frequency of intact SMAD4 and its association with patterns of therapy failure in patients with resected pancreas cancer. We reviewed the medical records of 516 patients who underwent upfront resection for clinically non-metastatic exocrine pancreas cancer at a single institution from 1995 to 2011. Of these, 127 patients’ surgical specimens were analyzed for SMAD4 expression. Tissue microarray samples were created from FFPE tissue blocks made from surgical specimens with immunostaining against SMAD4. A histoscore was created by the product of the percentage of cell staining and tumor intensity. A histoscore greater than zero was considered intact. Baseline patient variables as well as clinical outcomes including local progression, distant progression, and vital status were collected. Association of baseline characteristics and SMAD4 expression with clinical outcomes was evaluated using univariate Cox proportional hazard models. The median follow up and patient age were 5.7 years and 64 years, respectively. The median baseline CA 19-9 was 195. Most patients had ≥ T3 tumors (n = 95, 74.8%) and positive lymph nodes (n = 86, 67.7%). The rate of R1 and R2 resection was 16.5% (n = 21) and 1.6% (n = 2), respectively. All patients received adjuvant chemotherapy, and most patients received adjuvant chemoradiotherapy (n = 99; 78.6%). A total of 10 patients (7.9%) had intact SMAD4 expression. There was no significant difference in baseline characteristics between patients with intact SMAD4 and those with no SMAD4 staining. Local and distant progression occurred in n = 20 and n = 80 patients, respectively. Patients with intact SMAD4 had a higher rate of local progression than patients with no SMAD4 staining (OR 7.0, p <0.001, 95% CI 2.8-18.0). No other variables were significantly associated with local progression. Intact SMAD4 was not significantly associated with distant progression (OR 1.8, p = 0.062, 95% CI 0.97-3.2) or overall survival (OR 1.1, p = 0.73, 95% CI 0.6-2.2). LVSI was significantly associated with distant progression (HR 2.1, p = 0.01, 95% CI 1.2-3.8); otherwise, in this patient cohort no baseline characteristics were significantly associated with overall survival, local progression, or distant progression. In this large cohort, intact SMAD4 expression was associated with a higher risk of local progression. The infrequent detection (7.9%) of SMAD4 may limit its clinical utility. Prospective evaluation of the frequency of intact SMAD4 expression and validation of its predictive utility is warranted.