Integrated Systems and Technologies EarlierDetectionofBreastCancerwithUltrasoundMolecular Imaging in a Transgenic Mouse Model

While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MBVEGFR2) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n 1⁄4 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) usingMBVEGFR2 than nontargetedmicrobubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P< 0.001)whenbreast tissue (n1⁄4 315 glands) progressed fromnormal [1.65 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 1.16), DCIS (15.95 1.31), and invasive cancer (78.1 6.31) and highly correlated with ex vivo VEGFR2 expression [R 1⁄4 0.84; 95% confidence interval (CI), 0.72–0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78–88) and specificity of 89% (95% CI, 81–94). In a prospective screening trail (n 1⁄4 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosedmalignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) 1⁄4 0.98; 95% CI, 97–99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women. Cancer Res; 73(6); 1689–98. 2012 AACR.