Author Manuscript Published OnlineFirst on April 21, 2015; DOI: 10.1158/0008-5472.CAN-14-3361 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
B7-H3-Targeted Ultrasound Molecular Imaging for Breast Cancer Detection Sunitha V. Bachawal1, Kristin C. Jensen2, Katheryne E. Wilson1, Lu Tian3, Amelie M. Lutz1, Jürgen K. Willmann1
1
Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine,
Stanford, California, USA 2
Departments of Pathology, Stanford University, Stanford, California, USA and Veterans Affairs Palo Alto Health
Care System 3
Department of Health, Research & Policy, Stanford University, Stanford, California, USA
Corresponding Author Jürgen K. Willmann, M.D. Department of Radiology, Molecular Imaging Program at Stanford School of Medicine, Stanford University 300 Pasteur Drive, Room H1307 Stanford, CA 94305-5621 P: 650-723-5424; Fax: 650-723-1909 Email: [email protected]
Word Count: 4835 (excluding references); Number of Figures: 6; Number of Tables: 1 Conflicts of Interest: None Key Words: CD276; B7-H3, Targeted ultrasound imaging; breast cancer; microbubbles. Running Title: B7-H3-Targeted Ultrasound Molecular Imaging
1
Downloaded from cancerres.aacrjournals.org on May 4, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on April 21, 2015; DOI: 10.1158/0008-5472.CAN-14-3361 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abbreviations: ADH=Atypical ductal hyperplasia; ALH=Atypical lobular hyperplasia; ApoM=Apocrine metaplasia; CCL=Columnar cell lesion; DCIS=Ductal carcinoma in situ; FA=Fibroadenoma; FEA=Flat epithelial atypia; NPFCC=Non-proliferative fibrocystic changes; UDH=Usual ductal hyperplasia; Her2=Human epidermal growth factor receptor type 2 positive cancer; Luminal A=estrogen receptor and/or progesterone receptor positive cancer; Luminal B=estrogen receptor and/or progesterone receptor positive and Her2 positive cancer; Triple negative=estrogen, progesterone and Her2 negative cancer. B7-H3-targeted microbubbles (MBB7-H3); non-targeted microbubbles (MBControl); microvessel density (MVD) and receiver operating characteristic (ROC)
2
Downloaded from cancerres.aacrjournals.org on May 4, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on April 21, 2015; DOI: 10.1158/0008-5472.CAN-14-3361 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
ABSTRACT Ultrasound is a complimentary imaging modality to mammography in breast cancer detection in particular in patients with dense breast tissue, but is limited by its low diagnostic accuracy. Molecularly-targeted contrastenhanced ultrasound with microbubbles targeted at molecular signatures on tumor neovasculature is an emerging molecular imaging tool with great potential to improve diagnostic accuracy of ultrasound in breast cancer detection. In this study, expression of B7-H3, a member of the B7 family of immunoregulators, on tumor neovasculature of breast cancer versus normal, benign and precursor breast pathologies was assessed in a large-scale human immunohistochemical study, and feasibility of ultrasound molecular imaging using novel B7-H3-targeted contrast microbubbles for breast cancer detection was evaluated in transgenic mice. Immunohistochemical analysis of 248 samples, including normal breast tissues, 11 different benign and precursor breast pathologies, and 4 different subtypes of human breast cancer showed that vascular expression of B7-H3 was significantly higher in breast cancer (P
B7-H3-Targeted Ultrasound Molecular Imaging for Breast Cancer Detection Sunitha V. Bachawal1, Kristin C. Jensen2, Katheryne E. Wilson1, Lu Tian3, Amelie M. Lutz1, Jürgen K. Willmann1
1
Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine,
Stanford, California, USA 2
Departments of Pathology, Stanford University, Stanford, California, USA and Veterans Affairs Palo Alto Health
Care System 3
Department of Health, Research & Policy, Stanford University, Stanford, California, USA
Corresponding Author Jürgen K. Willmann, M.D. Department of Radiology, Molecular Imaging Program at Stanford School of Medicine, Stanford University 300 Pasteur Drive, Room H1307 Stanford, CA 94305-5621 P: 650-723-5424; Fax: 650-723-1909 Email: [email protected]
Word Count: 4835 (excluding references); Number of Figures: 6; Number of Tables: 1 Conflicts of Interest: None Key Words: CD276; B7-H3, Targeted ultrasound imaging; breast cancer; microbubbles. Running Title: B7-H3-Targeted Ultrasound Molecular Imaging
1
Downloaded from cancerres.aacrjournals.org on May 4, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on April 21, 2015; DOI: 10.1158/0008-5472.CAN-14-3361 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abbreviations: ADH=Atypical ductal hyperplasia; ALH=Atypical lobular hyperplasia; ApoM=Apocrine metaplasia; CCL=Columnar cell lesion; DCIS=Ductal carcinoma in situ; FA=Fibroadenoma; FEA=Flat epithelial atypia; NPFCC=Non-proliferative fibrocystic changes; UDH=Usual ductal hyperplasia; Her2=Human epidermal growth factor receptor type 2 positive cancer; Luminal A=estrogen receptor and/or progesterone receptor positive cancer; Luminal B=estrogen receptor and/or progesterone receptor positive and Her2 positive cancer; Triple negative=estrogen, progesterone and Her2 negative cancer. B7-H3-targeted microbubbles (MBB7-H3); non-targeted microbubbles (MBControl); microvessel density (MVD) and receiver operating characteristic (ROC)
2
Downloaded from cancerres.aacrjournals.org on May 4, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on April 21, 2015; DOI: 10.1158/0008-5472.CAN-14-3361 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
ABSTRACT Ultrasound is a complimentary imaging modality to mammography in breast cancer detection in particular in patients with dense breast tissue, but is limited by its low diagnostic accuracy. Molecularly-targeted contrastenhanced ultrasound with microbubbles targeted at molecular signatures on tumor neovasculature is an emerging molecular imaging tool with great potential to improve diagnostic accuracy of ultrasound in breast cancer detection. In this study, expression of B7-H3, a member of the B7 family of immunoregulators, on tumor neovasculature of breast cancer versus normal, benign and precursor breast pathologies was assessed in a large-scale human immunohistochemical study, and feasibility of ultrasound molecular imaging using novel B7-H3-targeted contrast microbubbles for breast cancer detection was evaluated in transgenic mice. Immunohistochemical analysis of 248 samples, including normal breast tissues, 11 different benign and precursor breast pathologies, and 4 different subtypes of human breast cancer showed that vascular expression of B7-H3 was significantly higher in breast cancer (P
