Prognostic Significance Of Immune Checkpoint Receptors In Node-Negative Breast Cancer

Background: Immune checkpoint blockade is increasingly discussed in breast cancer. We examined the prognostic significance of the immune checkpoint receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in node-negative breast cancer. Methods: Microarray based gene-expression data for CTLA-4 (221331_x_at) and PD-1 (207634_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CTLA-4 as well as PD-1 for metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal (ER + /HER2 - ), basal-like (ER - /HER2 - ) and HER2 + . Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of CTLA-4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.58, 95% CI 0.38-0.88, P=0.0102). Prognostic significance was most pronounced in the HER2 + positive molecular subtype (HR 0.23, 95% CI 0.08-0.65, P=0.0062) as compared to luminal (HR 0.68, 95% CI 0.39-1.18, P=0.1744) and basal-like (HR 0.53, 95% CI 0.25-1.15), P=0.1087) carcinomas of the breast. PD-1 RNA expression, however, was not associated with outcome in the whole cohort of patients (HR 0.88, 95% CI 0.32-2.43, P=0.1853). A trend for improved survival was noticed in basal-like breast cancer (HR 0.40, 95% CI 0.15-1.08, P=0.0701). Neither luminal (HR 0.81, 95% CI 0.28-2.36, P=0.2122) nor HER2 + (HR 0.85, 95% CI 0.27-2.68, P=0.7759) patients showed an association of PD-1 with MFS. CTLA-4 showed independent prognostic significance (HR 0.393, 95% CI 0.224-0.688, P=0.001) in multivariate analysis. In addition to CTLA-4, only histological grade of differentiation (HR 2.335, 95% CI 1.490-3.660, P Conclusions: The immune checkpoint receptor CTLA-4 has independent prognostic significance in node-negative breast cancer. Higher expression of CTLA-4 is associated with improved outcome. The prognostic impact of CTLA-4 differs between molecular subtypes and is most pronounced in HER2 + breast cancer. Citation Format: Schmidt M, van de Sandt L, Heimes A-S, Battista M, Lebrecht A, Almstedt K, Hoffmann G, Rahnenfuhrer J, Hengstler JG. Prognostic significance of immune checkpoint receptors in node-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-07.