Abstract 3831: Clinical significance of SMAD4 expression in resectable pancreatic cancer: correlation with tumor progression and recurrence pattern
Authors: Yamada Suguru , Fujii Tsutomu , Kanda Mitsuro , Sugimoto Hiroyuki , Nomoto Shuji , Kodera Yasuhiro 
Published: May 2015

Abstract
[Background]
SMAD4 is well recognized as contributing to pancreatic carcinogenesis. The recent studies suggest that SMAD4 expression pattern in pancreatic cancer is associated with tumor progression and eventual failure pattern. The SMAD4 protein expression is thought to be associated with a locally predominant progression pattern, whereas the loss of SMAD4 associated with distant metastases. In the current study, we validated the clinical significance of SMAD4 expression status as a biomarker of tumor progression and failure pattern in a large cohort of patients with resectable pancreatic cancer.
[Materials and Methods]
Surgical specimens were obtained from 174 pancreatic cancer patients who underwent resection at Nagoya University Hospital, Japan, during the period from April 2004 to March 2010. SMAD4 immunohistochemistry was performed in 174 patients and classified into SMAD4(+); staining or SMAD4(-); no staining. The correlation between clinicopathological parameters, failure pattern and prognosis was statistically analyzed.
[Results]
1. 59.8% of patients was SMAD4(-) (104/174), whereas, 40.2% of patients was SMAD4(+) (70/174). The disease-specific survival in SMAD4(+) patients was significantly better than that in SMAD4(-) patients (median survival time; 36.2 months vs. 14.3 months, P &lt; 0.001). SMAD4(-) had significantly more portal vein invasion, lymphatic invasion and neural invasion (P = 0.046, P = 0.029 and P = 0.035, respectively). Importantly, multivariate analysis revealed that SMAD4(-) was the most significant independent prognostic factor for pancreatic cancer.
2. In terms of the local spread pattern, the ratio of SMAD4(-) was 49.4% in the patients without vascular invasion, 61.9% in those with portal vein invasion, 76.5% in those with common hepatic artery invasion and 80.8% in those with superior mesenteric artery invasion, which showed the statistical significance (P = 0.013).
3. For postoperative failure pattern, the ratio of SMAD4(-) was 59.0% in the patients with local recurrence, 66.7% in those with both local and distant recurrence and 73.7% in those with distant recurrence, which showed that the patients who lost SMAD4 expression were more likely to have distant metastasis (P = 0.318).
[Discussion]
Our study demonstrated that the SMAD4 expression in resectable pancreatic cancer was a prognostic factor. The pancreatic cancer with SMAD4(+) was more likely to remain in local invasion, whereas, that with SMAD4(-) could develop to distant metastases. Preoperative assessment of SMAD4 expression in patients with resectable pancreatic cancer would support a treatment paradigm, where the local treatment like chemoradiation would be favored in patients harboring tumors with retained SMAD4 expression. On the contrary, systemic chemotherapy would be appropriate for the patients with absent SMAD4 expression.
Citation Format: Suguru Yamada, Tsutomu Fujii, Mitsuro Kanda, Hiroyuki Sugimoto, Shuji Nomoto, Yasuhiro Kodera. Clinical significance of SMAD4 expression in resectable pancreatic cancer: correlation with tumor progression and recurrence pattern. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3831. doi:10.1158/1538-7445.AM2014-3831