Clinical significance of CD73 expression in triple-negative breast cancer from the BIG 02-98 adjuvant phase III clinical trial

Abstract

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(s): 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. Participant(s): 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. Result(s): 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 tumorimmune 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.