Abstract
PurposeTo develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors.ProceduresIn this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in-house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), and mitochondrial oxygen tension (mitoPO2) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization.ResultsqBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO2 were associated with low MVD and vice versa. The heterogeneous pattern of MRO2 values showed spatial congruence with VSI. IDCs showed significantly higher MRO2 (P = 0.007), lower mitoPO2 (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors.ConclusionsWe developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity.
Highlights
Breast cancer (BC) is a complex disease with remarkable intratumoral heterogeneity which leads to varied genetic, phenotypic, and behavioral characteristics; clinical presentations; and treatment responses [1,2,3,4,5,6]
Tumor hypoxia has been recognized as an important feature and a key driver of BC heterogeneity [7] that leads to the development of cell clones and an aggressive and treatment-resistant phenotype characterized by rapid progression and poor prognosis [8]
Results quantitative BOLD (qBOLD) and vascular architecture mapping (VAM) data of good quality were obtained from 20 patients
Summary
Breast cancer (BC) is a complex disease with remarkable intratumoral heterogeneity which leads to varied genetic, phenotypic, and behavioral characteristics; clinical presentations; and treatment responses [1,2,3,4,5,6]. Tumor hypoxia has been recognized as an important feature and a key driver of BC heterogeneity [7] that leads to the development of cell clones and an aggressive and treatment-resistant phenotype characterized by rapid progression and poor prognosis [8]. To survive and grow in hypoxic conditions, tumor cells co-opt adaptive mechanisms, with a key mechanism being tumor neovascularization [10]. Tumor hypoxia and the induced neovascularization may provide powerful physiological stimuli that can be exploited as a tumor-specific condition, enabling the design of hypoxiabased imaging biomarkers and hypoxia-activated anti-cancer drugs. To date, the assessment of tumor hypoxia, neovascularization, and BC heterogeneity, and the ability to stratify patients based on the tumor’s hypoxia status is limited in its clinical application due to invasiveness [15] and poor reproducibility of the technique [16, 17], high costs (positron emission tomography, PET) [18,19,20], or low spatial resolution (near-infrared spectroscopy, NIRS) [21,22,23]
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