SMAD4 mutation acquisition in the metastatic transformation of pancreatic cancer.

Abstract

227 Background: SMAD4 mutations have been associated with worse prognosis and metastatic disease in patients with pancreatic cancer. It is unknown whether pancreatic cancers that metastasize acquire this mutation at disease onset or closer to the time of metastatic progression. Methods: Biopsies from 26 patients with known resectable and unresectable pancreatic cancer were analyzed via next generation DNA sequencing for 153 mutations associated with solid tumors, including SMAD4. Imaging and clinical data regarding extent of disease were reviewed at the time of each specimen collection. Results: 46% of patients had metastatic disease at the time of initial biopsy, and of these patients 83% had detectable SMAD4 mutations. Amongst patients with no evidence of metastatic disease, 11 of 14 had intact SMAD4. SMAD4 mutations were associated with metastatic spread of disease, Χ2= 7.46, p = .006. Eight patients with localized, SMAD4 intact pancreatic cancer had repeat biopsies at the time of metastatic progression that showed SMAD4 mutations not previously identified at the time of diagnosis. 2 of 3 patients with SMAD4 mutations and localized disease at diagnosis, developed metastatic disease within 7 months of biopsy. Mean time to metastatic disease development in localized disease patients with mutated and intact SMAD4 were 3.15 and 17 months, respectively, p = .01. Mean CA 19-9 levels in patients with mutated and intact SMAD4 were 10172 and 4117 U/mL, respectively, p = .04. Non-metastatic patients with SMAD4 mutations who developed metastatic disease shortly after initial biopsy only developed rising CA 19-9 levels once radiographic metastases were visible. Conclusions: SMAD4 mutations were ultimately acquired by each patient who presented with localized disease and then developed metastases, and are likely involved in the transformation from localized to metastatic disease. SMAD4 mutations are statistically associated with an earlier time to metastatic disease development in patients with localized disease at diagnosis. SMAD4 mutations precede CA 19-9 elevations in patients that develop metastatic disease and may represent a more sensitive biomarker to identify patients at greater risk for developing metastatic disease.