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Background: CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Several CD73 inhibitors and adenosine receptor antagonists are being evaluated in phase I clinical trials. Objective: To investigate the prognosis significance of CD73 in human triple-negative breast cancer. Design and setting: This is a prospective-retrospective biomarker analysis. Using multiplex immunofluorescence and image analysis, we assessed CD73 protein expression on tumor cells, tumor-infiltrating leukocytes and stromal cells on full-face sections from formalin-fixed paraffin-embedded primary breast tumors. Participants: 122 samples of triple-negative breast cancer from the BIG 02-98 adjuvant phase III clinical trial were included in our analysis. This trial compared the addition of taxanes to anthracyclines-based chemotherapy in node-positive breast cancer. Results: Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer. Using the median as a threshold between low and high levels of CD73 on epithelial cells, hazard ratios (HR) adjusted for grade, number of positive lymph nodes and tumor size, were of 2.21 (95% confidence interval (CI): 1.15-4.25); p=0.02 for DFS and of 2.47 (95%CI: 1.21-5.07); p=0.01 for OS. CD73 expression negatively correlated with tumor immune infiltration (Spearman's R= -0.50, p<0.0001). Patients with high levels of CD73 and low levels of tumor-infiltrating leukocytes had the worse clinical outcome (HR: 4.24 (1.90-9.45), p<0.001 for DFS, HR: 3.91 (1.65-9.31), p=0.002 for OS) compared to patients with low CD73 and high tumor-immune infiltration. Flow cytometric analysis of tumor-infiltrating leukocytes revealed a high frequency of CD73-expressing B cells and higher CD73 expression on tumor-infiltrating myeloid cells and natural killer cells compared to peripheral blood. Conclusion and relevance: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human triple-negative breast cancer and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this breast cancer subtype. Citation Format: Buisseret L, Pommey S, Allard B, Garaud S, Bergeron MA, Cousineau I, Ameye L, Paesmans M, Crown JPA, Di Leo A, Piccart-Gebhart M, Willard-Gallo K, Sotiriou C, Stagg J. Clinical significance of CD73 expression in triple-negative breast cancer from the BIG 02-98 adjuvant phase III clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-07.