Prognostic role and clinicopathological features of SMAD4 gene mutation in pancreatic cancer: a systematic review and meta-analysis

• PDAC is the gastrointestinal cancer with worst prognosis, even for the small percentage (15%) of people diagnosed with localized disease, the 5-year survival rate is only 44%. • Identifying PDAC-specific prognostic biomarkers for local and distant recurrence could result in more efficient PDAC diagnostic strategies. It could also lead to better selection of personalized therapy and, hopeful, to improved survival. • The prognostic role of SMAD4 status in patients with resectable PDAC is not clear. • Clarification of SMAD4 status prognosis value is needed to consider its potential integration in current selection criteria of eligible candidates to curative pancreatic surgery. The prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the prognostic value of the SMAD4 gene in pancreatic cancer to aid in the design of therapeutic strategies. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and the proposed methodology was registered on PROSPERO. An electronic search was made in MEDLINE (via PubMed), Web of Science and Google Scholar to identify all relevant studies. Eligible studies were those written in English including patients with Pancreatic Ductal Adenocarcinoma (PDAC), who underwent pancreatic surgery with curative intent and provided data on SMAD4 gene status or SMAD4 protein expression and its association to prognosis, measured by overall survival (OS). The effect measure of interest was the hazard ratio (HR) for OS between PDAC with or without SMDA4 mutations. A total of 24 studies on SMAD4 , with 4340 samples, were included in this systematic review and meta-analysis. Our pooled results demonstrated that patients with tumours with SMAD4 alteration had significantly worse prognosis for OS (HR= 1.43, 95% CI = 1.17–1.76, p-value = 0.002). This systematic review and meta-analysis support the use of driver mutations in the SMAD4 gene as a prognostic marker for pancreatic cancer.