Non-Invasive Assessment of Hypoxia and Neovascularization with MRI for Identification of Aggressive Breast Cancer.

Barbara Bennani-Baiti,Zsuzsanna Bago-Horvath,Paola Clauser,Thomas H. Helbich,Katja Pinker,Panagiotis Kapetas,Max Zimmermann,Andreas Stadlbauer,Pascal A. Baltzer

doi:10.3390/cancers12082024

Abstract

The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) for a non-invasive synergistic assessment of tumor microenvironment (TME) hypoxia and induced neovascularization for the identification of aggressive breast cancer. Fifty-three female patients with breast cancer underwent multiparametric breast MRI including quantitative blood-oxygen-level-dependent (qBOLD) imaging for hypoxia and vascular architecture mapping for neovascularization. Quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), mitochondrial oxygen tension (mitoPO2), microvessel radius (VSI), microvessel density (MVD), and microvessel type indicator (MTI) were calculated. Histopathology was the standard of reference. Histopathological markers (vascular endothelial growth factor receptor 1 (FLT1), podoplanin, hypoxia-inducible factor 1-alpha (HIF-1alpha), carbonic anhydrase 9 (CA IX), vascular endothelial growth factor C (VEGF-C)) were used to confirm imaging biomarker findings. Univariate and multivariate regression analyses were performed to differentiate less aggressive luminal from aggressive non-luminal (HER2-positive, triple negative) malignancies and assess the interplay between hypoxia and neoangiogenesis markers. Aggressive non-luminal cancers (n = 40) presented with significantly higher MRO2 (i.e., oxygen consumption), lower mitoPO2 values (i.e., hypoxia), lower MTI, and higher MVD than less aggressive cancers (n = 13). Data suggest that a model derived from OEF, mitoPO2, and MVD can predict tumor proliferation rate. This novel MRI approach, which can be easily implemented in routine breast MRI exams, aids in the non-invasive identification of aggressive breast cancer.

Highlights

Breast cancer is characterized by considerable heterogeneity, resulting in varying genetic, phenotypic and behavioral characteristics, clinical presentations, and treatment responses [1,2,3,4,5,6].This recognized tumor heterogeneity and the lack of understanding thereof significantly contributes to treatment failures and patient deaths [7,8]
We have recently developed a novel magnetic resonance imaging (MRI) approach for the non-invasive assessment of hypoxia and neovascularization in benign and malignant breast tumors, which can be integrated into a clinical MRI protocol, requiring less than seven minutes of additional scan time and no additional injection of gadolinium-based contrast agents (GBCAs) [15]
MRI measurement of tumor microenvironment (TME) hypoxia and neovascularity with quantitative blood-oxygen-level-dependent (qBOLD) and vascular architecture mapping (VAM) was successfully performed in all breast cancers

Summary

Introduction

Breast cancer is characterized by considerable heterogeneity, resulting in varying genetic, phenotypic and behavioral characteristics, clinical presentations, and treatment responses [1,2,3,4,5,6]. This recognized tumor heterogeneity and the lack of understanding thereof significantly contributes to treatment failures and patient deaths [7,8]. TME hypoxia and the induced neovascularization have been recognized as key drivers of the development of an aggressive and treatment-resistant tumor phenotype and are strong prognostic factors for disease progression, metastases, and survival [8,10]. Several studies have reported that microvessel density (MVD) is associated with poorer recurrence-free, cancer-specific, and overall survival [11,12,13] as well as with clinical response to chemotherapy [14]

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