Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging

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 contrast-enhanced 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 and benign 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 breast pathologies, and 4 different subtypes of human breast cancer showed that vascular expression of B7-H3 was significantly higher in breast cancer (P<0.001) compared to normal and benign pathologies. B7-H3 immunostaining on vessels could distinguish benign from malignant lesions with high diagnostic accuracy (AUC=0.90; 95% CI, 0.86, 0.90). In vivo B7-H3-targeted ultrasound molecular imaging signal was significantly (P<0.001) increased in breast cancer (49.4 ± 5.3 a.u.; n=146) compared to normal breast tissues (5.0 ± 0.5 a.u.; n=37) in transgenic mice and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence (R2=0.77, P<0.001). In conclusion, B7-H3-targeted ultrasound molecular imaging has great potential to improve diagnostic accuracy of ultrasound in detecting breast cancer in patients.