E. Katsuta1, L. Yan2, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Department Of Biostatistics And Bioinformatics,Buffalo, NY, USA
Introduction: CD73 is a surface enzyme that converts AMP into adenosine. Accumulated extracellular adenosine in tumor microenvironment generates immunosuppression and pro-angiogenic environment that promotes the onset and progression of cancer. Further, tumors that express high levels of CD73 have worse prognosis in some types of malignancies. However the impact of CD73 expression levels on breast cancer patient survival remains controversial. It was also reported that the impact of CD73 expression on patients survival was different among the subtype of breast cancer.
Methods: Gene expression was compared between cancer and non-cancer tissue using GENT (Gene Expression across Normal and Tumor tissue). Overall survival (OS) and disease-free survival (DFS) were compared between CD73 high and low expression groups based upon RNA-seq data of The Cancer Genome Atlas (TCGA) as the treatment- naïve cohort. Gene set enrichment analysis (GSEA) was conducted between CD73 high and low patients in TCGA. Relapse-free survival (RFS) was compared between CD73 high and low expression patients who received neoadjuvant chemotherapy using GSE25066 cohort. Gene expression was compared between before and after chemotherapy using GSE28844 cohort.
Results: CD73 expression level was significantly lower in cancer than normal breast tissue (p<0.001). Patients were classified as Luminal A (n=419), Luminal B (n=194), Her2 (n=67), Basal (n=140) and normal (n=24) by PAM50 classification. The expression of CD73 was significantly higher in Normal and Basal subtype compare to Her2, Luminal A, and Luminal B. Patients with high expression of CD73 showed worse survival compared with low expression group in both OS (5-year OS rate: 60.5% vs 83.4%, p<0.001) and DFS (5-year DFS rate: 71.5% vs 82.1%, p=0.049) in whole cohort, as well as in Luminal A+B patients OS (5-year OS rate: 54.5% vs 85.9%, p<0.001). However, there was no significant difference between these two groups neither in Her2 (p=0.180), Basal (p=0.962) or Normal (p=0.172) subtypes. High expression of CD73 group also showed worse relapse-free survival in neoadjuvant chemotherapy patients cohort (3-year RFS rate: 72.2% vs 83.6%, p=0.003). CD73 expression was significantly elevated in tumors after chemotherapy compared from before the treatment (p<0.001). It may imply that CD73 high expressed cells were resistant to chemotherapy. GSEA results revealed that epithelial-mesenchymal transition (EMT) and angiogenesis related gene sets were significantly enriched in CD73 high patient tumors.
Conclusion: Tumors with high expression of CD73 have worse prognosis in treatment-naïve patients as well as patients who underwent neoadjuvant chemotherapy. The worse prognosis of the patients with high expression of CD73 may be able to be explained by metastatic potential with up-regulated EMT as well as promoted angiogenesis.