Abstract B043: Impact of SMAD4 loss in patients with pancreatic ductal adenocarcinoma receiving neoadjuvant therapy
Authors: Racu Marie-Lucie , Bernardi Dana , Chaouche Aniss , Zindy Egor , Navez Julie , Loi Patrizia , Maris Calliope , Closset Jean , Van Laethem Jean-Luc , Decaestecker Christine , Salmon Isabelle , D'Haene Nicky 
Published: November 2022

Abstract
Introduction: SMAD4, the central mediator of the Transforming Growth-Beta (TGF-Beta) signaling pathway, is inactivated in 50-55% of pancreatic ductal adenocarcinomas (PDACs). SMAD4 loss of expression has been described as a negative prognostic factor in PDAC and associated with increased rate of metastasis and resistance to adjuvant therapy. However, the impact of SMAD4 inactivation in patients receiving neoadjuvant therapy (NAT) is not well characterized. The aim of our study is to investigate if SMAD4 loss is a prognostic factor in a cohort of patients who underwent surgery for PDAC and, more specifically, in patients receiving NAT. Material and methods: We analyzed a single center retrospective series of 204 patients who underwent surgical resection for PDAC between 2004-2021. SMAD4 nuclear expression was semi-quantitively assessed by immunohistochemistry (IHC) on tumor samples and related to clinical variables including overall survival (OS) and disease free survival (DFS). Results: Among the 204 patients, 64 (31,37%) received NAT and 140 (68,63%) did not. In the NAT cohort, 33 (51,47%) tumors were SMAD4-positive and 31 (48,43%) were SMAD4-negative and in the non-NAT group, 84 (60%) and 56 (40%) patients presented SMAD4-positive and -negative tumors, respectively (p=0.28). Both in the NAT and non-NAT cohort of patients, SMAD4 status was not associated with clinico-pathological variables and did not impact OS. However, regarding DFS, in patients without NAT, SMAD4 loss seems to be associated with shorter DFS (p=0.073). In a multivariate analysis including the significant clinico-pathological variables, SMAD4 status showed a tendency to remain an independent prognostic variable (p=0.052). Moreover, in patients that received NAT, univariate analysis indicated that SMAD4 loss was associated with worse DFS (p=0.018). However, in a multivariate analysis, only vascular invasion (p=0.02) and the subtype of administrated NAT (FOLFIRINOX or GEMCITABINE-based) (p=0.0004) were independent prognostic factors for DFS. We therefore evaluated the prognostic significance of SMAD4 loss in a homogenous group of patients receiving FOLFIRINOX-based therapy (n=45). Univariate and multivariate analysis indicated that in these patients, SMAD4 loss was an independent negative prognostic factor (p=0.009) as well as vascular invasion (p=0.003). Conclusion: This study highlights the potential prognostic role of SMAD4 loss in the DFS of PDAC patients, more specifically in patients receiving NAT.
Citation Format: Marie-Lucie Racu, Dana Bernardi, Aniss Chaouche, Egor Zindy, Julie Navez, Patrizia Loi, Calliope Maris, Jean Closset, Jean-Luc Van Laethem, Christine Decaestecker, Isabelle Salmon, Nicky D'Haene. Impact of SMAD4 loss in patients with pancreatic ductal adenocarcinoma receiving neoadjuvant therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B043.