Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy.Methodology/Principal FindingsFormalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166–0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280–0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells.Conclusions SignificanceLow miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.
Highlights
Pancreatic cancer is the fourth leading cause of cancer related death and over the last decades little improvement in survival has been observed despite extensive research efforts [1]
Significance: Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of Pancreatic ductal adenocarcinoma (PDAC) cases, and anti-miR-21 increased anticancer drug activity in vitro
Pathologic T3 stage tumors extend beyond the pancreas, without involvement of the celiac axis or superior mesenteric artery, whilst pT4 tumors are characterized by involvement of the celiac axis or the superior mesenteric artery
Summary
Pancreatic cancer is the fourth leading cause of cancer related death and over the last decades little improvement in survival has been observed despite extensive research efforts [1]. The role of adjuvant therapy in resectable pancreatic cancer is still unclear, though generally thought to benefit a subset of patients [4,5]. Being able to identify this subset would be a great advance in the management of this disease as it would allow patient stratification for adjuvant treatment [6]. Predictive markers of sensitivity to adjuvant therapy as well as new therapeutic targets are urgently needed in this disease [7,8]. Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Only a subset of patients benefit from adjuvant therapy. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy
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