Abstract P2-11-04: Expression of immune checkpoint related genes are prognostic in untreated breast cancer
Authors: Bianchini G , Rossi CM , Iwamoto T , Karn T , Callari M , Kelly CM , Pusztai L , Gianni L 
Published: August 2014

Abstract
Background
The prognostic and predictive relevance of different components of the adaptive immune system in HER2-positive, TN and high proliferation ER+/HER2- subtypes have been shown. In this scenario, the remarkable therapeutic efficacy of new immunomodulatory drugs targeting the immune checkpoints (i.e. CTLA4) provides attractive opportunities. We aimed to investigate the prognostic value of genes related to CD28 and CTLA-4 signaling pathways in early breast cancer patients.
Methods
We assessed the affymetrix gene expression data of 789 untreated, node-negative, early breast cancer patients. Expression of CTLA4, CD28 and the two corresponding natural ligands CD80 (B7-1) and CD86 (B7-2) were evaluated. The sum of these two ligands was combined as a unique marker (CDligs). The prognostic value of the three biomarkers and their interaction were assessed independently in each molecular subtype (ER-/HER2-, HER2+ and high proliferation ER+/HER2- [ER+/HER2- HP]). Multivariate analysis was adjusted for PGR, proliferation and other immune related genes (Tcell, IGG, MHC II, MHC I, Interferon and STAT1) (Gianni L, SABCS 2012). Distant event free survival was the outcome of interest.
Results
A significant moderately positive correlation was observed between each biomarker. Expression of CTLA4 and CDligs was higher in ER-/HER2- and HER2+ compared to luminal subtypes.
High expression of CTLA4 and CD28 were associated with lower risk of relapse in HER2+ (p = 0.008 and p = 0.03, respectively) and ER+/HER2-HP (p = 0.03 and p = 0.008, respectively). High expression of CDligs was also associated with lower risk of distant event in HER2+ group only (p = 0.01). No interactions were observed between CD28 and CTLA4 in any subtype. In both TN and ER+/HER2- HP subtypes, a significant interaction between CDligs and CTLA4 (interaction term p = 0.009 and p = 0.025, respectively), CDligs and CD28 (interaction term p = 0.028 and p = 0.008, respectively) and CDligs and Tcell metagene (interaction term p = 0.006 and p = 0.019, respectively) was observed. For instance, in high-CTLA4 group (above median cut point), higher expression of CDligs was associated with significantly lower risk of distant relapse in TN [HR 0.41 (0.21-0.82); p = 0.012], HER2+ [HR 0.25 (0.08-0.72); p = 0.011) and ER+/HER2- HP [HR 0.40 (0.29-0.85); p = 0.01] subtypes. Instead, in the low-CTLA4 group, CDligs was not associated with distant relapse in any subtype [TN, HR 1.80 (0.28-3.96) p = 0.141; HER2+, HR 0.69 (0.24-1.99) p = 0.495; ER+/HER2- HP, HR 1.28 (0.70-2.35) p = 0.425].
These interactions retain statistical significance in multivariate analysis including PGR, proliferation scores and other immune metagenes.
Conclusions
Genes related to the CD28/CTLA4 immune checkpoint are associated with risk of distant relapse independently of other biomarkers and immune related metagenes. A significant interaction between expression of ligands (CD80/CD86) and the two corresponding receptors CD28 and CTLA4 was found in TN and ER+/HER2- HP subtypes. These data confirm the complex interactions involved in the adaptive immune system regulation which may not be fully appreciated without consideration of biomarker interactions. They also provide additional evidence for exploring the use of immunomodulatory drugs in breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-04.