Genomic Signatures of Immune Activation Predict Outcome in Advanced Stages of Ovarian Cancer and Basal-Like Breast Tumors.

Ana Alcaraz-Sanabria,Francisco J Cimas,Mariona Baliu-Piqué,Antonio Casado,Katerin Rojas,Gloria Marquina,Cristina Saiz-Ladera,Aránzazu Manzano,Atanasio Pandiella,Balázs Gyorffy,Alberto Ocana,Pedro Pérez-Segura

doi:10.3389/fonc.2019.01486

Abstract

There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8+ T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.

Highlights

Ovarian cancer is still an incurable disease in its late stage [1, 2]
In ovarian cancer, the expression of CXCL13, INFG, CD30, and PRF1 genes predicted favorable prognosis, and that CXCL3, INFG, and PRF1 were associated with an increased infiltration level of CD8+ T cells and dendritic cells and neutrophils within the tumor
We evaluated the prognostic value of mRNA expression of each gene composing the different immune signatures and several gene combinations according to progression free survival (PFS) and overall survival (OS) in ovarian cancer patients with early (I and II) and advanced stage (III and IV) and in basal-like breast cancer tumors

Summary

Introduction

Ovarian cancer is still an incurable disease in its late stage [1, 2]. Several therapies have been explored and some have reached the clinical setting, improving survival, but not eradicating the disease [1, 2]. Even with the incorporation of these therapies metastatic ovarian cancer is still an incurable disease and novel therapeutics are necessary [2]. As described by gene expression analyses, the majority of tumors composing the basallike breast cancer subtype are triple negative breast cancers (TNBC). This subtype is represented by tumors that lack the presence of hormone receptors and HER2 overexpression on the cell membrane [4]. Basal-like breast tumors share some biological characteristics with ovarian cancers, such as a high genomic instability, and their inability to repair DNA, reflected in the presence of mutations in BRCA1/2 genes [4, 5]

Objectives

Methods

Results

Conclusion