Early Detection
New Methods
Until there is a cure or effective prevention for breast cancer, the best defense is early detection. The current status of detection is both impressive and disappointing. The primary screening is x-ray mammography which has high resolution but suffers from the use of ionizing radiation and a high false-positive rate (the number of tumors read from the mammogram as malignant that are actually benign). Biopsies are often performed to determine malignancy, which adds both expense and patient trauma. Although the existing detection technologies are impressive and provide the only means for detecting non-palpable cancers, from the patients perspective they are uncomfortable, ionizing and/or invasive technologies. It was a priority of the California Breast Cancer Research Program in Cycle I to seek significant improvement in current detection methods.
The means for improving current detection methods fall into two classes. The first represents significant improvements to the current process (e.g., reduction of the number of biopsies, improved mammography and reduction or elimination of exposure to ionizing radiation). The second class represents new approaches that use different measurement techniques to provide equal or better detection than x-ray mammography. Projects from both classes were funded in Cycle I.
The projects to improve x-ray mammography include a better detector system and the utilization of “digital” mammograms to improve care. The detector system increases the efficiency of converting rays into light. This has utility in both current film-based systems as well as in the emerging “digital” mammography units that use charge-coupled devices (CCDs) in place of film. The digital systems have the advantage that the image can be manipulated as a collection of numbers in a computer. This allows adjustments, such as changing the contrast settings, to be made after the data have been collected. The data can also be moved electronically over phone lines for remote viewing by consulting physicians or, eventually, consulting computers. It is hoped that the research in telemammography and computer-assisted diagnosis will lead to improved diagnosis and increased access to experts.
Several of the research projects seek to introduce new detection technologies that initially will complement x-ray mammography by reducing the number of benign biopsies. One approach is to tag drugs with agents that can be viewed with a nuclear medicine camera or with a positron emission (PET) camera. The marker drugs are designed to preferentially locate in cancerous areas of the body. The cameras can then noninvasively detect and localize malignant growths. One project focuses on a nuclear medicine scintillation camera and another project emphasizes PET cameras. Both studies seek to improve performance by customizing the technologies to the breast cancer application and reducing the size and cost of the cameras. Both projects also plan to demonstrate marker drugs for the breast cancer application.
Ultrasound is another technology that complements mammography as a means of reducing the number of benign biopsies and ultimately may be a screening technology by itself. This approach uses the reflection and/or transmission of acoustic waves to deduce the status of tissue inside the breast. Unlike x-rays, ultrasound is non-ionizing. One of the projects will use ultrasound to produce image “slices” of the breast that are analogous to x-ray computerized tomography(CT). Ultrasound does not currently have the spatial resolution of x-ray mammography-i.e., it cannot see objects as small as those seen on mammograms. However, there are potential interactions of the ultrasound with breast tissue that may obviate the need for comparable spatial resolution, and the resolution of clinical ultrasound units has steadily increased with time.
Rapid tumor growth usually requires the formation of new blood vessels. This development is known as angiogenesis and is a potential marker of cancer. Several projects in Cycle I seek to utilize angiogenesis as a means of detecting and treating breast cancer. One approach investigates using a label that is known to selectively bond to new vessels as a screening technique. Other projects utilize dynamic magnetic resonance imaging (dMRI) to detect microvascular status in the breast in conjunction with new drugs that preferentially permeate new vessels or magnetic labeling of blood flow in the breast. These approaches offer the promise of being noninvasive and non-ionizing---a significant improvement.
An alternative approach that does not utilize imaging is to detect changes in body chemistry. Two projects in Cycle I are pursuing this approach. One project is investigating increased protein production that occurs in a majority of breast cancer cells but not in normal breast cells. The project will determine the feasibility of using this for early detection. A second project is characterizing nipple aspirates of breast fluid. Changes that can be observed in the cells in the aspirate may be the basis for detecting and monitoring the progression of breast cancer.
The Cycle I projects represent a portfolio that aggressively pursues research leading to safer and more effective techniques for earlier detection and identification of the progress of breast cancer. A lot remains to be done and future cycles will continue to fund research in new and creative approaches for improving detection.
ABSTRACTS
Platelet Factor 4: A Marker for Malignant Breast Tumors
Per Borgstrom, Ph.D.
La Jolla Institute for Experimental Medicine
Angiogenesis, a fundamental process by which new blood vessels are formed, is rare in adults under normal physiological conditions. However, in pathophysiological conditions like cancer unrestrained angiogenesis occurs. Rapid tumor growth is dependent on angiogenesis to support the metabolic need of the fast-growing transformed tumor cells and the growth of the tumor beyond a certain size requires angiogenesis. In breast cancer there is a significant association between the density of vessels in the tumor (a consequence of the angiogenic process) and overall survival as well as relapse free survival in both node-negative and node-positive patients. Since the density of vessels in a tumor is an independent prognostic indicator in breast cancer, specific markers suitable for imaging of angiogenesis could contribute to the early detection of malignant breast tumors. We have previously shown that platelet factor 4 (PF4) selectively binds to newly formed vessels, i.e., sites of angiogenesis, and the overall goal of this project is to investigate the potential of PF4 as an imaging marker for breast cancer angiogenesis.
Our first goal is to characterize a suitable human breast cancer cell line using our newly developed in vivo video-microscopy technique. Our technique allows detailed repeated in vivo real time observations of tumor microvasculature, and permits quantitative evaluation of tumor growth and tumor angiogenesis in vivo. Currently there is no reliable information on in vivo angiogenic behavior of breast cancer, and the results from this investigation will inevitably provide new and important results which are a prerequisite for the evaluation of PF4 as an angiogenesis marker.
Our second goal is to investigate binding characteristics of systemically injected fluorescently labeled PF4 (FITC-PF4) to the microvasculature of human breast tumors. In the present investigation, we are using video-microscopy and fluorescently labeled PF4 which will allow us to characterize in detail the binding characteristics of intravascular PF4 which is a prerequisite for future use of other PF4 conjugates in clinical screening techniques. To the extent that we find that FITC-PF4 selectively labels the vessels of human breast cancer cell lines, such results would lend strong support for the use of PF4 as an in vivo marker for breast cancer angiogenesis. The proposed studies provide a systematic approach to evaluate the potential of PF4 as an imaging marker for breast cancer angiogenesis and thus could be an important step towards the development of novel screening techniques to improve the early detection of malignant breast tumors.
MRI Detection of Micro-vascular Status in Breast Cancer
Robert C. Brasch, M.D.
University of California, San Francisco
Favored possibilities to reduce breast cancer mortality and associated suffering include (1) the accurate detection of cancer at an earlier stage when the arrest of tumor growth and/or metastasis is more often successful, (2) a more effective utilization of available therapies to prevent progression, and (3) the institution of new and improved prevention strategies. The proposed research in this application and its clinical implementation have the potential to advance all three approaches. Program goals are to investigate the potential of a new class of diagnostic drugs, macromolecular contrast media, and new magnetic resonance imaging (MRI) techniques for improved detection and staging of breast carcinoma. The proposed MRI technique should provide high sensitivity and improved specificity for breast cancer detection over currently available detection methods. MRI, a technique which is decreasing in price and is becoming more widely available to the California patient population, offers several advantages over conventional radiographic mammography including absence of ionizing radiation, images in multiple planes, and superb soft tissue contrast; MRI is particularly beneficial for the 25% of women with radiographically dense breasts.
Small vessels within cancers are known to have unique anatomic and functional features; the new MRI techniques under development provide a non-invasive method to detect these pathologic microvascular characteristics. This project is relevant to the Priority Breast Cancer Research Issues in several ways. Knowledge about breast cancer micro vessels can be clinically useful (1) to permit earlier detection and more accurate differentiation of cancers from other mass lesions, (2) to determine the aggressiveness and metastatic potential of an individual cancer and thus to more accurately predict the clinical course, and (3) to choose the most appropriate drugs to prevent progression based on micro vessel permeability. A further benefit of this research should be the better understanding of breast cancer biology and specifically of tumor angiogenesis (growth of new vessel into tumors), a process critical to uncontrolled growth and metastasis of cancer. Dynamic MRI contrast enhancement patterns in four mammary cancers, presenting a spectrum of aggressiveness, microvascular densities, and endothelial permeabilities, will be compared to each other and to normal tissues. MRI techniques will be correlated with measured invasiveness including pathology, accumulation of antineoplastic drugs, and tracer kinetics. To improve the quantitative aspects and clinical practicality of the MRI microvascular characterizations, new and faster MRI acquisition and data analysis techniques will be tested and compared. The project is multi-disciplinary, requiring contribution in physics, chemistry, pharmacology, radiology, pathology and oncology.
Telomerase: A Factor for Early Detection of Breast Cancer
Nam Woo Kim, Ph.D.
Geron Corporation
According to recent research, normal cells have a predetermined lifespan controlled by the telomere. The telomere is a length of protective DNA that exists at the end of each chromosome and serves as a clocking mechanism that determines how many times a cell can divide and grow. In normal cells, the telomere shortens with each cell division, and when the telomere reaches a critically short length, the cell becomes “old” and stops dividing. Even in the presence of abnormal growth controls, the breast cancer cells will have a finite lifespan due to the shortening of telomeres. For a breast cancer to continue to grow, the cancer cells must prevent critical telomere loss and become immortal. The cancer cells accomplish this by producing telomerase, an enzyme which prevents telomere shortening.
We will evaluate telomerase expression using Geron's highly sensitive proprietary assay to test blood, lymph, needle biopsies, and banked tumor biopsies from breast cancer patients. The data gathered from these studies will help correlate telomerase activity with the presence and stage of cancer. We also expect to develop a second generation telomerase assay that will be easier and more cost-effective to perform, and can be used to detect telomerase positive cancer cells via microscopic examination of tissues. It is anticipated that our findings will result in more accurate and early detection of breast cancer, and a potential to predict which patients will experience more aggressive forms of the disease. This information can be used to reduce morbidity and mortality in breast cancer patients in California.
Investigation of Improved Drug Delivery in Breast Cancer
Orhan Nalcioglu, Ph.D.
University of California, Irvine
Improved delivery of diagnostic and therapeutic drugs to breast tumors is important for early detection and prevention of the progression of breast cancer. In this investigation, we will employ various vaso-active drugs to increase the preferential delivery of drugs to the tumors. If these drugs are used in conjunction with agents that are employed for imaging purposes they would increase the early detection accuracy of breast cancer. On the other hand, if they are used in combination with certain types of drugs for treatment they would deliver a larger proportion of their effect to the tumor while not damaging the surrounding normal tissues. The assessment of the accuracy of the new technique will be measured by dynamic magnetic resonance imaging (dMRI). The proposed investigation will specifically deal with the following CBCRP priority areas: (1) pathogenesis of breast cancer (breast cancer biology), (2) prevention of disease progression by predicting the outcome of treatment, and finally (3) improvement and early detection of breast cancer by exploiting vascular properties of such tumors. In order to achieve the above goals, we will exploit the fact that tumor microvasculature is hyperpermeable (hyper-leaky) to large molecular weight imaging and therapeutic drugs as compared with normal blood vessels. We will also use our previous finding that MRI techniques combined with pharmacokinetic modeling can be used to measure the permeability in tumors as a function of spatial location. We will test the effect of drugs that alter the permeability of tumor vessels temporarily so that large molecular weight agents can be trapped in the extravascular space and spend a longer time in the tumor. The proposed studies will employ animal tumor models to understand the performance of the proposed approach in controllable tumor models so that the application of the technique can be extended to breast cancer. Characterizing tumor permeability and other tumor transport parameters in breast cancer is important for the understanding of the pathogenesis of the disease, improved detection during the early stages due to the angiogenesis of neovasculature and corresponding vascular leakage, and in addition may aid in the prediction of bioavailability of chemotherapeutic agents to prevent the progression of disease. The successful outcome of the proposed research will positively impact all of the areas mentioned above.
Cripto: A Breast Cancer Marker?
Christina C. Niemeyer, Ph.D.
La Jolla Cancer Research Foundation
The purpose of this project is to study cripto, a protein produced at elevated levels in a majority of human breast cancer cells but not in normal breast cells. Cripto is a growth factor for breast cells and can cause morphological changes. Thus, it is a good candidate for a breast cancer marker and could be used in the earlier detection of the threat of cancer. However, very little is known about its role in mammary gland development and during the various stages of breast carcinogenesis. Before any marker for mammary carcinogenesis can be used in early detection strategies, prior knowledge of its mode of activation is essential. Also important is determining how it can be detected. The long term objectives of this project are to determine the role cripto plays in mammary gland carcinogenesis and ascertain its use as a diagnostic marker for breast cancer. Knowledge gained from this study of Cripto will also open an avenue for prevention strategies.
Questions, hypotheses, and methods: (a) Is the over production of cripto an initiation event or are the elevated levels observed later in tumorigenesis? The time course during various stages of tumor formation and progression will be studied in mice that produce mammary tumors caused by the over production of oncogenes. Cripto activation possibly precedes the onset of cancer and therefore can be used as a marker of tumor-precursor cells. (b) Can chemical agents modulate cripto production and thus the transforming ability of cripto over production? Cripto production is decreased by retinoic acid in certain cells. The effect of clinical treatment agents such as retinoids, tamoxifen, and selenium will be assayed. (c) Does over production of cripto in mammary cells lead to abnormal mammary growth and does it act with other known onco-genes? Cripto will be over and under produced in a mammary cell culture to test the effect of aberrant cripto production on cultured mammary cells' potential to become tumorigenic or grow abnormally. Cells over producing cripto will be transferred into normal mouse mammary fat pads and the cells allowed to develop into gland. The effect of cripto on mammary development and the effect that components of the normal mammary gland have on cripto over-producing cells will be tested. The question of whether cripto acts synergistically with other known oncogenes will also be studied.
Breast Cancer Incidence in Women With Abnormal Cytology
Margaret R. Wrensch, Ph.D.
University of California, San Francisco
Breast cancer is a leading cause of death among women in California and the United States. Early diagnosis is considered to be a key factor to minimize mortality; thus, techniques to identify high risk women are essential.
Although methods to identify women with inherited susceptibility to breast cancer are becoming more promising, they are not yet routine and only 5%-10% of breast cancer cases are likely to be due to inherited susceptibility. Breast cancer risks associated with specific histologic findings in benign breast biopsies have been quantified, but fewer than 15% of women who develop breast cancer have had a prior breast biopsy. Mammography has limited predictive value in women under age 50 when used without regard to other risk indicators. Nipple aspiration of breast fluid is a simple, non-invasive way of obtaining fluid from breasts of women who are neither pregnant nor lactating. Breast cells in this fluid can be classified as either normal or as showing various abnormalities, including hyperplasia (a increase in the number of cells in a tissue or organ which results in an enlargement of the area), atypical hyperplasia, and cancer. We previously followed 3170 women who participated in breast fluid studies between 1972 and 1980. Women with proliferative cytology (i.e., hyperplasia or atypical hyperplasia) were significantly more likely to develop breast cancer through April, 1991 than women with normal cytologic findings in nipple aspirates of breast fluid or than women from whom fluid could not be obtained. Results were strongest and most consistent for women under age 55 at time of nipple aspiration.
In this study, we will determine the breast cancer incidence and mortality for 3170 women from the original cohort over the period May, 1991 through December, 1996. We will also determine breast cancer incidence, through December, 1996 in 4,080 additional women with known nipple aspirate cytology who participated in breast fluid studies between 1980 and 1991. Information from this new study will be used to augment our initial findings on the prognostic value of cytologic findings in nipple aspirates of breast fluid in identifying women at high risk of breast cancer. Incorporating nipple aspirate cytology findings with other indicators of breast cancer risk represents an innovative approach to identifying women at high risk of breast cancer for either intensive clinical management or for epidemiologic studies of prevention or progression of breast cancer.
This study has immediate relevance to the CBCRP priority issue of early detection of breast cancer and to the identification and careful characterization of women at high-risk of breast cancer; it also will provide a data source of risk factors, breast cancer cases, and a large pool of women from which to choose controls for studies of genetic markers of breast cancer susceptibility and progression.
Hybrid Grid Detector for Early Detection of Breast Cancer
John M. Boone, Ph.D.
University of California, Davis
The early detection of breast cancer is presently the single most important factor in terms of improving the prognosis of individuals stricken with the disease. Screen-film mammography is currently the best technology for discovering early breast cancer. However, it is widely recognized that significant improvements can be made to conventional screen-film detectors, and such improvements can lead to even earlier detection of breast cancer. A Hybrid Grid- Detector is the topic of this research. This system is designed to specifically improve the detectability of breast cancer. The hybrid-grid detector should allow physicians to visualize breast cancer at an earlier phase of development, which will improve treatment prognosis and reduce mortality.
The current generation of x-ray sensors, including the conventional screen-film cassette presently used for mammography, use a two-step process for x-ray detection. First, an x-ray is absorbed in an x-ray phosphor, which emits visible light after the x-ray is absorbed. Second, the visible light is detected by a sensor that is light sensitive, for example film. Newer, digital sensors such as Charge Coupled Devices (CCDs) can also be used as the light sensor for digital mammography. Coupling the x-ray phosphor with a CCD sensor, however, leads to loss of light because of the optics needed (e.g., lenses). The proposed hybrid grid-detector design should markedly increase the amount of light released by the x-ray phosphor, improving spatial and contrast resolution. Spatial resolution is the ability to see very small objects, such as the microcalcifications that are present in about 40% of breast cancers. Contrast resolution is the ability to see objects that have subtle contrast, such as the breast tumor itself. The research plan involves computer simulations of the system, construction of the detectors, and evaluation of their performance in the laboratory. The hybrid detector is constructed of a very fine (0.05 mm) honeycomb of leaded glass, with the pores packed with x-ray phosphor. A special fluid will fill the rest of the pore, allowing efficient light propagation. The glass partitions will also absorb unwanted scattered x-ray radiation. The pores will conduct light without lateral spreading to improve spatial resolution. By increasing the light output, reducing x-ray scatter, and enhancing the spatial resolution, the contrast resolution will be improved.
The hybrid grid-detector should lead to a significant advance in imaging performance, with concomitant gains in the early breast cancer detection capability of mammography.
Noninvasive Measurement of Blood Flow Through Breast Tumors
Michael H. Buonocore, M.D., Ph.D.
University of California, Davis
Early detection of malignant (cancerous) tumors and discrimination from benign (non-cancerous) tumors can reduce human and economic costs by reducing the number of missed malignant breast tumors and reducing the number of biopsies performed on benign tumors.
The specific aim of the project is to develop and test a new noninvasive Magnetic Resonance Imaging (MRI) technique for measurement of blood flow through breast tumors. MRI (a technique based on the interaction of hydrogen protons with magnetic fields) has been proposed as a screening tool and our technique would make such screening more specific for malignant tumors. Our hypothesis is that malignant tumors can be distinguished from benign tumors by measurement of the higher blood flow through the malignant tumors. We plan to establish a definitive diagnosis via tissue biopsy which will be made in all subjects and will establish the technique's potential for early detection and diagnosis of malignant tumors.
Blood flow through tissue is referred to as tissue perfusion and measured in milliliters per minute per gram of tissue. The proposed MRI technique is referred to as arterial spin-tagging, first reported in 1992 for brain tissue perfusion. In this technique, flowing blood, prior to entering the tumor, is magnetically labeled and observed by imaging within the tumor. Greater flow into the tumor causes greater image intensity changes compared to images obtained without magnetic labeling. Enhanced angiogenesis (growth of blood vessels) of malignant tumors is the reason for the increased flow, and appears to be a reliable discrimator of benign versus malignant tissue. Arterial spin tagging techniques will show MRI signal enhancement in malignant tumors similar to that shown in dynamic contrast-enhanced MRI, in which signal enhancement results from passage and accumulation of contrast material. Arterial spin-tagging offers greater sensitivity and higher reliability because it can be applied repeatedly to systematically investigate the tissue parameters. It is not limited to observations over a single pass.
The technique may also reduce the incidence of false-negative diagnoses by revealing high tissue blood flow in small tumors that are not observable with standard MRI or other modalities. The technique may have an important role in detection of small tumors at multiple distinct locations that change management. In larger tumors, this technique may be useful to reveal optimal biopsy sites, which will reduce the number of falsely negative biopsies and the total number of negative biopsies.
A Non-Invasive Method of Locating Malignant Breast Tumors
Edward J. Hoffman, Ph.D.
University of California, Los Angeles
Mammography is accepted as the best means of screening for non-palpable breast cancer. However, signs of breast cancer, such as microcalcifications or masses, seen for most malignant tumors, are also seen with many benign tumors. Thus, while mammography will locate about 85% of all cancers, only about 30% of the tumors that are read as cancerous in mammograms are actually malignant. Most of the biopsies now performed, therefore, would not be necessary if the benign (non-cancerous) tumors could be distinguished from malignant tumors (cancerous) by non-invasive techniques.
We propose to develop and test a small nuclear medicine camera, which, in combination with the nuclear medicine imaging agent, Tc-99m-Sestamibi, can locate and identify malignant breast tumors. This camera can be placed in a mammography suite, and used after a suspicious finding is seen by mammography. Recent reports on detection of malignant breast tumors using Tc-99m-Sestamibi show that the tumor was detected more than 90% of the time, and correctly identified as malignant more than 90% of the time. We believe that our camera will surpass the performance of these standard cameras. It will be much smaller, it would be capable of being brought in close to image the breast at angles that would avoid the high background from the Tc-99m-Sestamibi, which also accumulates in heart and liver. The camera is a miniature scintillation camera with a 5 cm by 5 cm field of view. (Scintillation cameras transform the energy from radioactive decay particles into light images.) Standard scintillation cameras are 50+ cm in diameter and 30 cm deep, weighing 1000 lbs+. The small camera can view the breast from above or below, the camera can be placed under the arm for a medio lateral oblique view, etc. In each case the field-of- view is free of the activity of the body. For testing, the camera will be fitted to the stereoscopic mammography system designed for core breast biopsies, and images will be obtained of the mammograph-ically positive region on women who are undergoing a biopsy. In this manner the technique will be tested by comparison with the universally accepted procedure for determining malignancy. The goal is to eventually replace a significant fraction of the biopsies using Tc-99m-Sestamibi scans with the miniature camera in the mammography suite.
It is our hypothesis that the improvement of the technique made possible by our new camera could make this a cost effective procedure which will significantly reduce the number of unnecessary biopsies that are performed because of the lack of specificity of mammography. The procedure would be less costly than both core and excisional biopsies, and less risky than the excisional biopsy.
Real Time Telemanagement of Mammography Examinations
H. K. Huang, D.Sc.
University of California, San Francisco
Breast cancer is the fourth most common cause of death among women in the United States. There is no known means of preventing the disease, and available therapy has been unsuccessful in reducing the national mortality rate over the past 60 years. Current attempts at controlling breast cancer concentrate on early detection by means of mass screening, using periodic mammography and physical examination, because ample evidence is now available to indicate that such screening indeed can be effective in lowering the death rate. However, scarcity of trained experts hinders a better mammography screening delivery system. Real time digital telemammography emerges as a primary candidate to alleviate this problem. In real time digital telemammography, the mammogram is first converted to a digital image at the examination site, transmitted to a breast imaging expert center through telecommunication where trained mammo-graphers are available for immediate consultation. The specific aims of this research project are to develop a real time telemammography system and to study the effectiveness of the system by setting up a test bed in the San Francisco Bay area. The success of this project will allow a better mammography screening delivery system.
Two hypotheses will be tested: (1) telemammo-graphy technologies can be developed for routine real time clinical operation, and (2) real-time tele-management can be established for mammography practice. In order to test these two hypotheses, four topics will be studied: Telemammography Technologies, Telediagnosis, Teleconsultation, and Telemanagement. Telemammography technologies will be investigated by setting up a telemammo-graphy chain between a satellite site at Mt. Zion Hospital (a community-based hospital) and the Breast Imaging Center at the University of California, San Francisco as the expert center. The developed methodology will first be used for tele- diagnosis, and then for teleconsultation. Teledia-gnosis is a response by the expert within 24 hours, whereas teleconsultation is within half an hour. The ultimate goal of telemammography is telemanage-ment which is defined as the remote real-time management and interpretation of mammography examinations performed at the satellite site by mammography specialists at the diagnostic center.
By the end of this three year study, we intend to have validated a standard real time telemammo-graphy protocol. The methodology could then be extended to other mammography screening programs in California for timely diagnosis by experts. This, in turn, would provide a better health care delivery system for the earlier diagnosis of breast cancer for Californians.
Breast Imaging with an Ultrasound CT Scanner
George R. Leopold, M.D.
University of California, San Diego
Breast cancer is a major health care problem that affects an increasing number of younger women. X-ray mammography provides an excellent tool for diagnosis but has a high false positive rate (i.e, wrongly indicating the existence of a cancer tumor) and is possibly even less sensitive in women with dense breasts. Sonography, or ultrasound (a diagnostic technique in which deep structures of the body are visualized by recording the reflection of high frequency sound waves) is an attractive way to examine questionable areas detected on the mammogram, but it is complicated to perform. Furthermore, modern high-resolution sonography instruments image only a small portion of the breast at a time and it is often difficult to identify the suspicious region.
We have developed an ultrasound computed tomography (USCT) scanner that makes cross-sectional images of the breast (CT is a technique that uses computer technology to generate images of thin “slices” of tissue from multiple views around all sides of the object). These novel images are similar to optical holograms and are based on fundamentally different principles from that of conventional sonography. Our new approach uses circular rings of up to 1024 transducers (devices that change sound waves into electrical signals) that surround the entire breast. A single cross-sectional image covers a very large area eight inches (20 cm) in diameter and requires less than one second to acquire. In preliminary studies, this system has been able to display very small details (0.5 mm at 1 MHZ) over a very large image field of view.
This research will examine the suitability of this technique for breast imaging and will examine its ability to identify the many types of lesions in the breast. Two groups of volunteers will be recruited for study: (1) subjects referred for mammography screening will expand our experience with normal anatomy for a wide range of breast types, and (2) subjects with confirmed breast lesions will be studied along with x-ray mammography and sonography for comparison.
This technology has the potential to improve the early detection of breast cancer and to reduce the number of unnecessary biopsies.
Novel PET Cameras for Earlier Detection of Breast Cancer
William W. Moses, Ph.D.
Lawrence Berkeley National Laboratory
The aim of this project is to develop PET (positron emission tomography) cameras whose geometry is optimized for earlier detection of breast cancer or axillary node involvement. These postmammo-graphy tools would: (1) determine whether suspicious structures observed in mammograms have the increased metabolism or chemistry associated with breast cancers; and (2) image the metabolic activity in the axilla (armpit) to determine the extent of axillary node involvement.
The proposal intends to develop new instrumentation to extend an existing nuclear medicine tracer technique. With this technique, a biologically active drug containing a radioactive isotope is injected into the patient. In this case, the drug is FDG (fluoro-deoxyglucose), which is similar to sugar in that most cells that metabolize sugar also attempt to metabolize FDG. However, FDG is not metabolized easily, so it “sticks” in cells that are actively metabolizing sugar. Most breast cancer cells have a much higher glucose (sugar) metabolic rate than normal tissue, so the concentration of FDG in a tumor is typically 8 times higher than in normal tissue. The FDG contains an isotope (I8F) that radioactively decays by emitting a positron (the anti-particle of an electron). When the positron comes in contact with an electron (from the patient), they annihilate and form a pair of back-to-back gamma rays that exit the patient. Instrumentation that detects these pairs of gamma rays are known as PET cameras (positron emission tomography) and use the direction that these gamma rays are coming from to form an image of those places in the body in which the FDG has accumulated.
Using conventional PET cameras that image the entire body, FDG has been shown to be an excellent tracer for breast cancer, with >95% specificity (i.e. probability that it concentrates sufficiently in a tumor to be detected) and >90% selectivity (i.e. probability that it only concentrates in cancerous tumors and not in benign, or non-cancerous ones). The proposed instruments only image the breast or armpit regions, but have higher efficiency (up to 30 times greater), finer spatial resolution (0.9 mm), and lower cost (possibly by a factor of 10) than conventional PET cameras.
This technological advance has the potential to provide a cost effective, non-invasive alternative to biopsy as well as accurate information on axillary node involvement that is not available from existing techniques. It also has the potential to be used as a screening technique (especially for patients with dense breasts) or in follow-up studies to evaluate the effect of therapy.
New Imaging Modality For Early Detection of Breast Cancer
William M. Pardridge, M.D.
University of California, Los Angeles
This work attempts to develop a non-invasive diagnostic test that allows for the early detection of breast cancer. This new approach will merge three methodologies in the biological sciences: tumor-specific monoclonal antibodies, radiographic imaging of radiolabeled antibodies, and antibody cationization. The novel feature of the proposed work is the use of cationized antibodies as radioimaging probes for human breast cancer. The original promise of monoclonal antibodies as “magic bullets” has not been realized for a variety of reasons. However, a significant factor is the lack of access of the monoclonal antibody in the blood circulation to the tumor antigen buried within the breast tumor. This lack of access is due to the very slow egress of very large proteins, such as monoclonal antibodies from the blood compartment across the barrier lining the tiny capillaries that perfuse the tumor. Even antibody fragments are too large to significantly cross tumor-capillary barriers.
The present application will use a new antibody delivery technology that allows circulating antibodies to rapidly cross capillary barriers and cell membranes and enter the intracellular spaces to access intracellular antigens. The model monoclonal antibody that will be used in these studies is a monoclonal antibody to the p185HER2 oncogenic protein. This gene is amplified in at least 30% of human breast cancer and is of prognostic significance.
The antibody delivery technology to be used in these studies is antibody cationization. This antibody delivery technology will allow the p185HER2 monoclonal antibody to enter into the intracellular compartment of the cancer cell. Antibody cationization involves chemical modification of the surface of the antibody to give it “positive charge” which causes the antibody to interact with “negative charges” on the surface of cells to trigger uptake by the cell. The cationized monoclonal antibody will then be radio-iodinated using an isotope that can be detected by external detection technologies available in standard radiographic clinics, such as single photon emission computed tomography (SPECT).
It is possible that following both the cationization and radio-iodination, the monoclonal antibody will no longer retain access to the p185HER2 oncogenic protein. Therefore, these one year studies will test the feasibility of making these modifications in the monoclonal antibody in such a way that the antibody's high affinity for the target oncogenic protein is retained. Following initial in vitro experiments in tissue culture using breast carcinoma cell lines grown in petri dishes that express the p185HER2 oncogenic protein, in vivo studies in mice will also be performed. These in vivo studies will examine the rate of clearance and tissue uptake of the radio-iodinated monoclonal antibody in both its native and cationized forms. It is hypothesized that when experimental breast cancer is planted as solid tumors in the mice, the “signal/noise” imaging ratio of the radio-iodinated, cationized antibody will be at least a log order of magnitude increased over the signal/noise ratio of the radio-iodinated, native monoclonal antibody. If so, cationized antibodies will be a much more sensitive modality for imaging breast carcinoma as compared to native or conventional antibodies.
Electronic Imaging for Hospital and Community-Based Mammography
Daniel J.Valentino, Ph.D.
University of California, Los Angeles
Early detection is crucial in reducing the economic and human costs of breast cancer. Digital mammography, which generates electronic images of the breast instead of the traditional photographic films, offers a significant advance in the early detection and diagnosis of breast cancer. In addition to providing earlier detection, digital mammography will facilitate the use of advanced computer programs to help all California women obtain more prognostic breast cancer examinations. The goal of this project is to develop an innovative computer information system to provide cost-effective digital mammography in a hospital or community clinic.
The proposed system includes the following technological advances, many of which have been developed in our laboratory and will be evaluated for use with digital mammography: direct digital acquisition and storage of whole-breast images; lossless image compression (reducing the size of images without losing any information); and “intelligent” image management including the integration of images, radiology reports, and medical records; and an innovative computer workstation. We will develop an innovative workstation that we call the “virtual view box”. The virtual view box allows a radiologist to view pairs of images, and quickly switch to other images for additional comparisons; this is ideally suited to the rapid comparisons that mammographers currently perform using film. We will develop new electronic tools to optimize the brightness and contrast of the images depending upon the density of the breast and type of lesion; as well as to rapidly view reports and image databases. We will use a rapid prototyping technique to develop and implement the mammography workstation so that it accommodates the actual tasks the mammographer is required to perform. Finally, the proposed system will facilitate the use of other advanced digital technologies, such as teleradiology (providing radiological services remotely) and computer-aided diagnosis (programs that provide additional diagnostic information to radiologists), by providing a digital environment in which computerized tools can help doctors screen more patients at lower cost.
The primary benefits of this system will be the ability to quickly and accurately screen young women under the age of 50; the decreased cost of operating digital systems versus film-based systems; and a unique potential to provide improved access for under served populations via the use of a mobile digital mammography unit and teleradiology to provide subspecialist diagnosis to poor and minority women. In addition, using computerized tools that are being developed by institutions across the nation, digital mammography can improve the detection of suspicious lesions during screening. The intended result of this research is a test-bed for whole-breast digital mammography that, working with medical industry leaders, will be used to ensure that digital mammography products will be widely available to benefit California women.
USC/Norris Breast Cancer Research Training Program
Ronald K. Ross. M.D.
University of Southern Calitornia
This proposal seeks support to establish a Breast Cancer Research Training Program at the University of Southern California USC/Norris Comprehensive Cancer Center (NCCC). The NCCC has a long history of breast cancer research, formalized in recent years as the NCCC Breast Cancer Research Program, but has never had a formal, focused, interdisciplinary graduate research training program devoted to breast cancer.
The proposed program seeks to take advantage of the extraordinary racial/ethnic diversity among the 9 million residents of Los Angeles County, the population served by the NCCC. Our goal is to better understand the reasons for the underlying differences in breast cancer incidence, mortality and survival among the numerically most important of these racial-ethnic groups in the County (African-Americans, Latinas, Japanese, Chinese, Filipinos, Koreans and non-Latina whites). We envision a multi-faceted approach involving epidemiology and prevention scientists, behavioral scientists, tumor biologists, and molecular geneticists, and radiation. surgical and medical oncologists. We will use the numerous patient and data resources available to us to achieve this goal. These include the Los Angeles County SEER cancer registry program; a large registry of breast cancer in twins; dietary and lifestyle data from recently characterized large racial/ethnically diverse cohorts; a large and diverse clinical population seen at NCCC affiliated hospitals, and several large tumor and other biological sample banks for studies of tumor biology and molecular genetics.
We describe and document in this application the commitment of the NCCC to establish this Training Program: we summarize the research resources available for training graduate students for breast cancer research; we describe the evaluation process for applicants; and we overview the planned organizational structure of the Training Program relative to the NCCC overall, including advisory groups and their functions.
