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Page 4 of 7 Neumann et al. J Cancer Metastasis Treat 2018;4:13 I http://dx.doi.org/10.20517/2394-4722.2017.60

Table 1. Comparison of AR2A and AR2B expression and survival in basal like breast cancers
Median OS DMFS Median DMFS
OS log rank low/high Hazard ratio Log rank low/high Hazard ratio
P-value expression P-value expression
AR2A 0.012 40.8/97.5 0.52 (0.31-0.87) 0.0008 18/97.5 0.42 (0.25-0.71)
AR2B 0.011 95.1/41 1.96 (1.15-3.32) 0.0004 102.6/23 2.16 (1.127-3.67)

Overall survival (OS) and distant metastasis free survival (DMSF) were compared and median survival calculated using km plotter. For
OS 241 patients and for DMFS 242 patients were analyzed

A A2AR A2BR
B
11 9.0
10 9 8.5
8.0
Log2 expression 8 7 Log2 expression 7.5
7.0

6 6.5
6.0
5 5.5
Basal Her2 LumA LumB Normal like Basal Her2 LumA LumB Normal like
(n = 328) (n = 238) (n = 719) (n = 490) (n = 200) (n = 328) (n = 238) (n = 719) (n = 490) (n = 200)

Figure 2. Comparison of A2AR (A) and A2BR (B) expression among Pam50 breast cancer subtypes in the METABRIC. A2BR is
significantly higher expressed in basal like breast cancer compared to other breast cancer subtypes (***P = 3.9e-11). Gene expression
data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were
downloaded from the Gene expression Omnibus database [GEO: GSE62944] and Synapse software platform (syn1688369; Sage
Bionetworks, Seattle, WA, USA), respectively

OS and distant metastasis free survival (DMFS) with a median survival for high expressors of 41 and
23 months, respectively. However, patients that expressed high levels of A2BR had a median OS of
95.1 months and a DMFS of 102.6 months, respectively [Table 1]. This is in contrast to high A2AR expression
which seems to prolong overall survival in the basal breast cancer group [Table 1]. All in all, these findings
suggest a functional difference between these two receptors in basal-like breast cancer. The term basal-like
breast cancer is often used as a surrogate for identifying the aggressive TNBC subtype. Close to 80% of the
[31]
basal like breast cancers are TNBC . As TNBC is defined by lacking ER, PR and HER2, the basal subtype, is
characterized by a distinct gene expression signature comprising strong expression of basal markers such as
[32]
cytokeratins 5,6 and 17 .

Evidence already exists that blocking adenosine signaling may be a valuable option in treating TNBC.
The A2BR ligand adenosine is produced in sequential action of CD39 and CD73 degrading ATP. Both
are surface receptors expressed on cancer cells and like A2BR, induced by oxygen deprivation (hypoxia).
In contrast to CD-39, CD73, also known as 5’-nucleotidase, is similar to A2BR, higher expressed in
the ER-negative breast cancer population compared to the ER-positive cancers (METABRIC data base;
P = 3.6e-14). This suggests a close co-operation of the two receptors in TNBC progression. In fact,
mouse models have clearly demonstrated that CD73 expression promotes resistance to TNBC to
[33]
anthracyclins and poor prognosis . This has now been confirmed in human patients as data from
the BIG-02-98 study conclude that high levels of CD73 expression on epithelial tumor cells positively
associates with reduced DMFS and OS and negatively correlates with tumor immune cell infiltration
(Spearman’s r = -0.50, P < 0.0001). Patients with high levels of CD73 and low levels of tumor-
[34]
infiltrating leukocytes had the worse clinical outcome . This suggests that adenosine signaling
in TNBC associates with poor patient survival and that targeting CD73 or A2BR may provide a