E. Katsuta1, S. N. Hochwald2, K. Takabe1 1Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Gastrointestinal Surgery, Department Of Surgical Oncology,Buffalo, NY, USA
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most aggressive cancers with five year survival less than 10%. This is a reflection of the fact that PDAC is refractory to current treatment and novel targets for therapy are in urgent need. Recently, cancer stem cells and epithelial–mesenchymal transition (EMT) have been proposed to be one of the mechanisms of drug resistance that leads to poor survival. CD73 (5'-nucleotidase) degrades AMP into adenosine that results in the generation of an immunosuppressed and pro-angiogenic tumor microenvironment that promotes the onset and progression of cancer. CD73 is also known as one of the essential mesenchymal stem cell markers. Given these roles, we hypothesized that CD73 expression in PDAC is associated with survival.
Methods: Clinical and RNA-seq data were all obtained from the Cancer Genome Atlas (TCGA). Of the 170 PDAC cases with tumor RNA-seq, 169 cases were usable for overall (OS) and 130 cases were usable for disease-free survival (DFS) analysis, respectively. Tumors were classified as either high or low expression of CD73 by the mean value. Sex, age T and N factor, histological grade, tumor location and CD73 expression were analyzed to identify patterns of tumor recurrence and factors that predict survival. Cox proportional hazard regression model was used for multivariate analysis.
Results: High expression of CD73 in the tumor was significantly associated with larger tumor size (4.2cm vs 3.6 cm; p=0.021). Interestingly, CD73 highly expressed cases demonstrated significantly worse survival in both OS (median 15.8 months vs 21.4 months; p=0.004) and DFS (median 9.6 months vs 17.3 months; p<0.001). On univariate analysis, residual tumor (R1, 2; p=0.008) and CD73 high expression (p<0.001) had a significant association with worse DFS. Multivariate analysis demonstrated that the independent factors negatively impacting DFS were residual tumor (p=0.045) and CD73 high expression (p=0.011). Lymph node metastasis (p=0.017), residual tumor (p=0.011) and CD73 high expression (p= 0.004) had a significant association with worse OS on univariate analysis. Multivariate analysis demonstrated that residual tumor (p=0.025) and CD73 high expression (p=0.007) were also related with poor OS. Correlation analysis revealed that CD73 expression was correlated with cell cycle related genes such as E2F7 (R = 0.65) and cancer stem cell related genes such as MET (R = 0.63). Only weak correlation was seen with epithelial–mesenchymal transition (EMT) related genes such as SNAI2 (R = 0.42) and TMEM132A (R = 0.42). No correlation was seen between CD73 and immune system nor angiogenesis related genes.
Conclusion: Tumors with high expression of CD73 have larger tumors and worse overall and disease free survival in PDAC. CD73 expression levels correlated with cell cycle related genes and cancer stem cell related genes, but not with immune system or angiogenesis factors.