High SMAD4 Expression is Associated with Improved Clinical Outcomes in Patients with Resectable Pancreatic Cancer: An Analysis of NRG Oncology/RTOG 9704

Purpose The SMAD4 transcription factor mediates TGF-β signal transduction and is frequently inactivated in pancreatic cancer (PC). This study evaluated SMAD4 (protein) expression in the NRG Oncology/RTOG 9704 phase III trial comparing post-operative chemotherapy-chemoradiation combination regimens for resectable PC. It is hypothesized that higher SMAD4 expression correlates with lower distant metastasis (DM) and improved overall survival (OS).Materials and methods Quantitative multiplexed SMAD4 immunofluorescence analysis was performed in pan-cytokeratin positive tumor samples from resected specimens. Total cellular SMAD4 analysis was dichotomized by the median (low: Results For 141 analyzable patients, baseline characteristics remained similar with and without SMAD4 quantitation and between low and high SMAD4 groupings. High SMAD4 expression was associated with better DFS (32% risk reduction of DFS failure [HR (95% CI): 0.68 (0.48, 0.97); p=0.03]), improved OS (31% risk reduction of death [HR (95% CI): 0.69 (0.48, 0.99); p=0.04]), and lower DM rates [HR (95% CI): 0.69 (0.48, 0.99), p=0.048], but not LRR. Multivariable analysis confirmed correlations between high SMAD4 and better DFS [HR (95% CI): 0.66 (0.46, 0.96), p=0.03] and lower DM rate [HR (95% CI): 0.68 (0.46, 1.004), p=0.052].Conclusions SMAD4 expression is significantly associated with lower DM and higher DFS and OS in tumor samples from a large, prospectively randomized trial of resectable PC.