Abstract B09: High TGFβ1 expression may ameliorate the poor survival associated with high KRAS expression in patients with resectable pancreatic carcinoma

Abstract

Abstract The precise role of transforming growth factor beta type 1 (TGFβ1) in the progression of pancreatic carcinoma (PC) is unknown, and the relationship to survival is context dependent (referred to as the TGFβ paradox where TGFβ expression in early tumors is a favorable characteristic and a detrimental characteristic in advanced tumors). It has been suggested that loss of TGFβ1 expression may allow for KRAS mutant induced development of PC from IPMNs. We hypothesized that survival in patients with resected PC is shorter in high KRAS and high TGFβ1 expressing PC. Clinical data, tumor DNA sequence, and mRNA expression data was acquired from The Cancer Genome Atlas data set. Inclusion criteria were complete data available, pancreatic adenocarcinoma or ductal carcinoma histology, and underwent pancreaticoduodenectomy. Patients were divided into high and low gene expression based on the 75th percentile of mRNA expression for each gene. Overall survival was investigated with the Kaplan-Meier method/log-rank test and multivariate Cox proportional hazard ratio (HR). Overall, 106 patients were identified with an average age of 65 ± 11 years and 58% of patients were male. The median follow up time was 15 months (range 0.3 months to 75 months). Low TGFβ1 expression was associated with median survival of 17 months while median survival was not reached for the high TGFβ1 expression group (at least 60 months, P = 0.007). For all patients, high expression of KRAS was associated with worse survival (16 vs 20 months, P=0.03). However, there was no association between KRAS expression and survival in the high TGFβ1 expression group (P = 0.2) whereas in the low TGFβ1 expression group, high KRAS expression was associated with worse survival (12 vs 20 months, P = 0.012). On multivariate analysis, high TGFβ1 expression was associated with improved survival (Cox HR= 0.36, P=0.01) while high KRAS expression was associated with worse survival (Cox HR= 1.73, P = 0.050). When investigating survival by KRAS expression (high/low) and TGFβ1 expression (high/low), the longest survival was seen in KRAS high / TGFβ1 high expressing tumors while the shortest survival is seen in KRAS high / TGFβ1 low expressing tumors (overall P = 0.002). All long-term survivors (> 40 months) were in the high TGFβ1 expression group. In patients who undergo pancreaticoduodenectomy for pancreatic carcinoma, this data suggests that the TGFβ1 paradox may be related to KRAS expression. High TGFβ1 expression may be able to ameliorate the worse survival associated with high KRAS expression in these patients. Further work is needed to delineate the mechanism of this interaction, investigate it in patients with advanced PC, and identify opportunities to modulate intra- and extra-cellular TGFβ1 signaling to improve survival. Citation Format: Evan Scott Glazer, Eric Welsh, Jamie Teer, Mokenge P. Malafa.{Authors}. High TGFβ1 expression may ameliorate the poor survival associated with high KRAS expression in patients with resectable pancreatic carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B09.