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A New MRI Dextran-Based Contrast Agent for Early Detection and Diagnosis of Breast Cancer
Background: In a series of highly-respected papers, Brasch et al. at UCSF used MRI blood pool contrast agents to detect experimental breast tumors. The mechanism for this detection was the increased permeability of the contrast agent into the breast cancer due to leaky cancerous vessels. A limitation of this work was the inability to select a MRI contrast agent. Brasch was limited to MRI agents based on albumin and other macromolecules larger than 70kD. An agent with an optimal size that would be small enough to rapidly leak into the breast tumor, but large enough not to leak into normal tissue is needed. We developed a new chemical technology which permits us to select the size of the agent.
Objective/hypothesis: We will test the hypothesis that the tumor permeability of our new dextran-based MR contrast agent will correlate with histopathologic tumor grade and microvessel density (MVD).
Specific aims: To test a new MR contrast agent for the detection and characterization of breast cancer.
Study Design: We will synthesize a MR contrast agent that has approximately 40 kD in molecular weight. Based on known diffusion measurements of experimental tumors, these agents should exhibit a factor of ten increase in tumor accumulation when compared to the current MR blood pool agent (70 kD and larger). A spectrum of rat mammary tumors, from benign to malignant, will be induced by administration of N-ethyl-N-nitrosourea (ENU). We will image 40 rats with breast-tumors in a 1.5 Tesla MR scanner with our new agent and with gadopentetate (a low molecular weight agent) 48 to 72 hours apart. We will measure tumor permeability as the endothelial transfer rate constant Kps. The Kps measurement will be obtained by applying a three-compartment pharmacokinetic model to the MRI time-enhancement data. The tumors will be graded using the Scarf-Bloom-Richardson (SBR) method and the MVD will be evaluated with anti-CD31 immunohistochemical staining. We will then use ROC analysis to compare the diagnostic power of the two contrast agents. We will also correlate the Kps to the MVD.
Potential Outcomes and Benefits of the Research: An MRI contrast agent that is specific for breast cancer and exhibits prolonged enhancement will, with a new generation of dedicated breast MRI scanners with biopsy capability, permit simultaneous detection and histologic diagnosis. The highest impact will be for women at high risk with mammograms of poor diagnostic quality and women previously diagnosed with breast cancer, but whose mammogram either did not visualize the lesion or grossly underestimated the size.
Current imaging techniques for Breast Cancer Detection and Diagnosis lack both sensitivity and specificity, and X-ray mammogram, the most prevalent breast cancer screening method, fails to detect approximately 30% of breast cancers. Magnetic Resonance Imaging (MRI) can detect cancers that are not visible on a mammogram. However, both methods often are unable to distinguish cancer from a benign (non-cancerous) lesion. Therefore 53 – 80% of breast biopsies prompted by MRI prove benign. Cancerous tissue has a different vascular structure than benign tissue including leaky vessels due to aggressive angiogenesis. Current MR contrast agents have a small molecular weight and leak into surrounding areas of both normal and cancerous tissues. The ideal agent should have an optimal molecular weight that leaks into malignant tumors but not into benign lesions.
The long-term goal of this project is the earlier detection of breast cancer via MRI guided biopsy. We will synthesize a dextran-based MR contrast agent using a technique established in our laboratory. This agent will permeate and remain in the tumor so that the MR image can be used to guide a biopsy needle. We will test the ability of the new contrast agent for prolonged enhancement of breast cancer. The current contrast agent has low tumor specificity and after enhancement, leaves the tumor. This latter characteristic makes MRI guided biopsy difficult. Prolonged tumor enhancement by our new agent would present a better target for the biopsy needle. Although more expensive than a mammogram, MRI is now used in academic centers for breast cancer detection in high-risk women with mammograms of poor quality due to high tissue density.
We will also test the hypothesis that the leak of the new contrast agent into breast tumors will help diagnose breast tumors, and that the degree of leak will correlate with the histology of the tumors. We will use a rat breast tumor model that develops different kinds of breast tumors from benign to malignant. We will image 40 rats with breast tumors with our new agent, and with gadopentetate (a standard agent for MRI with a low molecular weight). We will employ a kinetic model previously developed for contrast accumulation by experimental breast tumors. We will then use a statistical analysis technique to compare the diagnostic power of the two contrast agents. Lastly, we will employ a histolopathology grading system previously used for experiments in breast cancer in rats to correlate the permeability of both agents.