Abstract P3-05-09: mRNA expression level and prognostic significance of different immune-related biomarkers in early breast cancer
Authors: Martini Veronica , Favero Francesco , Corà Davide , Varughese Feba , Sica Antonio , Gennari Alessandra 
Published: March 2020

Background: The combination of an anti-Programmed Cell Death-Ligand-1 (anti-PD-L1) agent, atezolizumab, plus chemotherapy (CT) as first line treatment in triple negative (TN) advanced breast cancer (ABC), resulted into a significant improvement in Progression Free Survival (PFS) as compared to Nab-paclitaxel alone, and a significant improvement in Overall Survival (OS) in the PD-L-1 positive subgroup (&gt; 1% by IHC). With these results, the IMpassion 130 study met its primary endpoint, although its impact on the prognosis of TN ABC is less than expected, suggesting that innovative approaches are needed to maximize the role of immunotherapy in this disease subset. In this perspective, the potential role of addressing innate immunity as opposed to adaptive immunity has not yet been evaluated. It has been shown that Tumor-Associated Macrophages (TAMs) may express the immune checkpoint inhibitor PD-L1, thus contributing to immunosuppression. In addition, in response to microenvironmental signals they acquire a tumor-promoting M2-like phenotype, that supports angiogenesis, tissue remodeling and metastasis formation. They also express the Signal-regulatory protein (SIRPα) which provides a “don’t eat” me signal that impairs phagocytosis of CD47 positive cancer cells. CD47 is expressed in all human solid tumor cells; its role is to protect cancer cells from being recognized by innate immune surveillance. With these premises, the aim of this study is to evaluate the expression and prognostic value of different biomarkers related to innate and adaptive immunity, by using publicy available gene expression datasets, to assess if double immune co-targeting (i.e. innate and adaptive) might represent a viable strategy to optimise immunotherapy in ABC.

Methods: We used previously published gene expression datasets by two online tools: GOBO and GEPIA. GOBO is an ultrafast tool including 1881 early BC patients generated on Affymetrix U133A microarrays, with a median follow up of 120 months. Expression of CD47, SIRP, CD163 and CD204 (M2-like phenotype) mRNA were evaluated as continuous variables. Kaplan Meier survival curves were used to assess the prognostic ability of the identified biomarkers. GEPIA is a web server for analysing the RNA sequencing expression data of tumours and normal samples from the TCGA and the GTEx projects, by a standard processing pipeline.

Results: CD47 and CD204 mRNAs were significantly overexpressed in BC samples with respect to normal tissues (p &lt; 0.05). Furthermore, CD47, SIRPalpha and CD163 were differentially modulated in the different BC subtypes (p&lt;0.00001), showing an increased expression in the basal like group. Finally, the expression of mRNA CD47, SIRPa and CD163 were associated with a significanly worse OS only in the luminal A subtype (p&lt;0.008, p&lt;0.05 and p&lt;0.01, respectively).

Conclusions: These results indicate that innate immunity is involved in BC prognosis, and might be considered a target for therapy, in particular in those subtypes such as the Luminal A group, characterised by a favourable outcome; conversely, no effect was observed in subtypes characterised by a worse prognosis such as the basal-like tumors. Further investigation on the role of innate immunity in BC is warranted.

Citation Format: Veronica Martini, Francesco Favero, Davide Corà, Feba Varughese, Antonio Sica, Alessandra Gennari. mRNA expression level and prognostic significance of different immune-related biomarkers in early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-09.