Downregulation of SMAD4 Is Significantly Associated with Poor Prognosis of Pancreatic Cancer: A Clinicopathologic Study of 643 Cases in a Single Cancer Center
Wai Chin Foo, Milind Javle, Yanan Li, Siddhartha P Kar, Veera Baladandayuthapani, Xiaoqun Dong, Donghui Li, Dongfeng Tan. University of Texas, M.D. Anderson Cancer Center, Houston, TX
Background: SMAD4 and transforming growth factor (TGF) ß are important biomarkers in pancreatic cancer. TGF-ß exerts its effects through the TGF-ßR1/ R2 receptors and the SMAD transcriptional regulators. We investigated the prognostic value of these related biomarkers in pancreatic cancer.
Design: 643 total patients were studied retrospectively. TGFßR2 and SMAD4 protein expression were measured in available pancreatic cancer biopsies using immunohistochemisty (IHC). IHC was evaluated for intensity (0: none, 1: weak, 2: moderate, 3: strong) and percentage of positive tumor cells (0: 0%+, 1: 1-10%+, 2: 10-25%+, 3: >25%+). The final IHC score was then calculated (intensity x percentage). Plasma TGFß1 level was also measured using the Meso Scale Discovery Multi-array® Human TGFß1 Assay. The relationship between IHC score and overall survival (OS) was assessed using multivariate Cox proportional hazards models with relevant clinical covariates. Kaplan-Meier and log-rank tests were also used to analyze OS by plasma TGFß1 levels.
Results: In the multivariate Cox model, after adjusting for baseline stage, CA 19-9, PS, age, and TGFßR2 expression, complete loss of SMAD4 expression (IHC score 0) was significantly associated with lower OS (HR: 1.85, 95% CI: 1.06-3.23; p = 0.03). Progressive disease on a first-line gemcitabine-base regimen was more likely in loss of SMAD4 group as compared with retained SMAD4 group (score higher than 0) (46.5% vs. 38.1% progressed; chi square p = 0.069). In patients with locally advanced and metastatic disease, a significant difference in OS (27.7 weeks compared to 40 weeks) between the top quartile of plasma TGFß1 levels (>19.05 ng/mL) and lower levels, respectively (log-rank p = 0.0125, adjusted).
Conclusions: This large retrospective study suggests that downregulation of SMAD4 plays a role in prognosis of pancreatic cancer. Assessment of SMAD4 by readily available immunohistochemistry may have potential utility to evaluate the clinical outcome of this malignancy.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 288, Tuesday Afternoon