Early Detection

Until there is a cure or it can be prevented, the best defense against breast cancer is early detection. The current status of detection is both impressive and disappointing. The existing detection technologies are impressive in their ability to find very small tumors, and they provide the only means for detecting non-palpable cancers, but from the patient's perspective they are uncomfortable, ionizing and/or invasive technologies. The primary screening technique is x-ray mammography which has high resolution but suffers from the use of ionizing radiation and a high false positive rate (the fraction 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. It is a priority of the California Breast Cancer Research Program to significantly improve current detection methods.

BCRP funded thirrteen grants in Cycle II dealing with improving the early detection of breast cancer. The studies fall into three categories. The first is technology-oriented: either improving existing technologies for the early detection of tumors, or developing new technologies; the second, based on molecular and cell biology based studies, is to either uncover new biomarkers that can be used to assess the risk of breast cancer or detect its presence, or to develop new biological agents which can be used in conjunction with various technologies to improve detection; and the third involves socio-behavioral and health policy approaches that attempt to understand and improve compliance behaviors by women, or to improve the organization and delivery of early detection services.

BCRP funded five projects that are oriented at the technology, or instruments, used in early detection. Two of these projects will attempt to advance x-ray mammography (the current "gold standard" in early detection) by improving the efficiency of that part of the system that converts the energy of the X rays into the light needed to expose the x-ray film. Both systems would result in a lower dose of X rays being needed, and would largely eliminate the need for the patient to be x-rayed again to obtain a better image. Three projects seek to introduce new detection technologies that initially will be used to further examine abnormalities seen on x-ray mammograms, to reduce the number of benign (and therefore ultimately unecessary) biopsies. One approach is to tag drugs designed to preferentially locate in cancerous areas of the body with agents that can be viewed with a nuclear medicine camera (using gamma rays) that will be redesigned specifically for use in breast imaging. Another approach is to design a positron emission (PET) camera dedicated to breast imaging only, thus avoiding the problems of whole-body PET scanners adapted for breast imaging. Both projects seek to improve performance by customizing the technologies to 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. Finally, one project attempts to work out problems of tissue characterization by light which are crucial to the development of a non-invasive detection technique that does not use ionizing radiation. The instrument itself would use infrared light to look at breast tissue and distinguish normal from abnormal tissues.

There are four studies which employ molecular and cell biology in an alternative approach based on changes in body chemistry. The first two attempt to create novel agents which should improve the "picture" of the lymph nodes obtained using imaging techniques. Another study will use a fragment of a monoclonal antibody to deliver a radioisotope to the cancer cell. (Antibodies are components of the blood which circulate and bind onto certain molecules on cells "foreign" to the body and potentially harmful to it. Once bound, other blood cells such as macrophages can find and destroy them.) The particular problem is to label the antibody without inactivating it.

The last study in this group will assess the value of a recently-discovered biomarker (a substance which is created as a product of certain cell functions--in this case those of a cancerous cell) in predicting which women who have undergone cancer treatment and show no evidence of the disease will have a recurrence. The investigators will also evaluate whether this marker can predict which cases of in-situ (non-invasive) cancer will go on to become invasive.

There are two proposals in the social science arena addressing the early detection issue. The first will test a means of improving the use of mammography by African American women (for whom mortality rates have failed to improve to the extent that they have improved for other women) in an underserved area of Los Angeles. The other study is a large, ambitious study attempting to draw lessons from other countries to improve the delivery and efficacy of mammography screening services throughout California.

Finally, one grant will initiate a formal training program to increase the number of breast cancer researchers in California. Complementing the program initiated last year at the University of Southern California, which focused on epidemiology, this UCLA-based program will have its research emphasis on imaging technologies.

The Cycle II Projects continue the direction taken in the first cycle by funding a portfolio of grants that aggressively pursues research leading to safer and more effective techniques for earlier detection, as well as access to, and delivery of, these services.


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Research Program Awards


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Improving Access to Mammography in an Urban Underserserved Area

Bruce Allen, Jr. Dr.P.H.
Charles R. Drew University

One of the BCRP's priority areas is a focus on research that can specifically benefit underserved populations. This priority coincides perfectly with the mission of the Charles R. Drew University -- to conduct medical education and research in the context of service to a defined population so as to train persons to provide care with competence and compassion to this and other underserved populations. This study will improve and expand the earlier detection of breast cancer for a currently underserved urban population by developing more effective, low-cost interventions in a manner which may be used for other underserved areas throughout the state.

The Charles R. Drew University Cancer Center and the UCLA-Jonsson Comprehensive Cancer Center have come together to collaboratively conduct a three-year study of how to increase the use of screening mammography among African American and Latino women. The purposes of the study are to: 1) determine the prevalence of screening mammography in African American and Latino women 40 years old or older who reside in the King/Drew Medical Center South Central Los Angeles service area; and 2) implement and evaluate the effectiveness of using a culturally-specific telephone intervention designed to increase participants' self-efficacy, increase their knowledge about the importance of regular mammograms, identify and modify their intentions to undergo screening, and provide women with information to counter their reasons for not having a mammogram.

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Harnessing Technology To Improve Mammography Effectiveness

Laura Esserman, M.D.
University of California, San Francisco

One of the goals of the BCRP is to determine the best approaches to prevent death from breast cancer, and to most effectively spend its resources to accomplish this goal. We believe this must include the broad implementation of high quality mammographic screening throughout the state. The specific purpose of this grant is to investigate the factors required to achieve high cost-effectiveness in mammography screening in California, and then develop a plan to promote the provision of the highest quality screening services for the least possible cost.

As health care delivery systems change, we need to develop ways to decrease the cost of delivering services, and to maintain high quality. Regionalization and organization strategies for mammography have the potential to markedly improve the quality, and to markedly decrease the human and economic cost of mammographic screening. The emergence of newer technologies, such as digital mammography and telemammography which integrate advances in computerized medical imaging and telecommunications, will provide an opportunity to improve the efficiency of mammography screening by allowing for regionalization without requiring a major overhaul in our current system of health care delivery. (Regionalization is a system of health services delivery which enables the benefits of the expertise and technologies available in the most advanced medical centers to "flow" down to community hospitals and neighborhood health centers.) Digital mammography has the potential for improvement over traditional mammography by increasing clarity and reducing technical errors, film noise, film processing artifacts, and variability in interpretation of mammograms. Telemammography has the potential to significantly improve the quality of breast care by allowing a greater percentage of patients access to the "expert mammography" available in the best medical centers.

We propose, in the first year, to undertake a more thorough investigation of the underlying basis for what leads to 'expert' interpretation of mammography tests and the degree to which false positive readings can be minimized. Our research will include the evaluation of European systems as well. During the second and third years,we will examine the distribution of patients, providers, and payers for mammographic services in Northern California, re-evaluate the technical developments in digital and telemmamography, and analyze the costs of implementing a shared network for mammographic services. We will then devise a strategic plan to introduce the technology which will include incentives to enable cost sharing to promote the highest quality of services for the least cost within the context of the realities of the health care delivery market place in California in the late 1990's. Clearly, the delivery of health care is undergoing profound change and we will need innovative strategies to assure quality of care. By combining both a scientific and a market-based analysis of the "business" of providing mammographic services, California will be able to use mammographic screening as an example of how changes in organization can lead to significant improvements in care by decreasing the cost, raising the quality of service, and increasing the number of women served.

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TIMP-3, An Early Indicator of Breast Cancer

Susan Hawkes, Ph.D.
University of California, San Francisco

The long-term objective of this research is to define how cells in a tissue within the body interact with one another and what happens to these interactions when some of the cells become cancerous. Several years ago my laboratory discovered a novel protein which has the potential to play several roles in the development of cancer. This protein, called TIMP-3, is produced in significant amounts at various stages in the development of a fetus but not by most normal cells in an adult. Production of this protein appears to be switched on again during the development of cancer. We propose that TIMP-3 may be a useful marker for breast cancer.

TIMP-3 has several functions. It is capable of helping to prevent the destruction of structural components of tissues which sometimes accompanies the development of a tumor. On the other hand, it is also capable of stimulating cells to divide and increase in number. Furthermore, it encourages cells to break away from one another. Both of the last two properties facilitate the development of a tumor, whereas its protective effect on tissue architecture would have the opposite effect. One aim of the present grant application is to unravel this apparent paradox and to determine the exact role that TIMP-3 plays in cancer progression. This will be accomplished by use of different types of cells from the human breast that will grow under laboratory conditions.

Cancer is a multi-stage process and cells which display properties characteristic of five different stages of the disease (from early to late) will help us to determine at what stage the production of TIMP-3 may be important. Regardless of its precise role in this process, we already know the synthesis of TIMP-3 is turned on early in the conversion of normal cells to cancer cells derived from animal tissues other than breast. We have also studied sections of human breast tissue from women with malignant and benign disease and those who have undergone surgery for breast reduction. Using an immunological reagent (antibody) which binds specifically to TIMP-3, we have probed 26 samples for the presence of this protein. All malignant cancers (17 cases) contained TIMP-3, whereas none of the normal tissues or benign tumors (9 cases) showed the presence of this protein. A second major aim of this proposal is to study a very large number of pathology specimens encompassing a wide spectrum of breast disease to determine if the presence of TIMP-3 can be used as a diagnostic tool for a pre-malignant or early stage of the disease in tissue biopsies.

A particularly interesting observation that we have made is that TIMP-3 is present in breast fluid within apparently normal ducts adjacent to invasive tumors. This raises the exciting possibility of monitoring nipple aspirates for the presence of TIMP-3. Nipple aspiration is a relatively simple, non-invasive means of obtaining small volumes of fluid from women who are neither pregnant nor lactating. We have developed a very sensitive test for measuring the activity of the protein and have demonstrated the feasibility of this approach by showing that nipple aspirates from healthy women volunteers (6 studied) contain predominantly TIMP-1, some TIMP-2 (related proteins), but no TIMP-3. We predict that TIMP-3 activity will be detectable in nipple aspirates from women with invasive cancer and possibly earlier stages of the disease as well. Thus, a third aim of this application is to screen nipple aspirates from healthy women, those at particular risk for developing cancer and those who already have evidence of malignant and benign tumors. We propose to determine if the presence of TIMP-3 in this biological fluid correlates with a particular diagnosis or stage of breast cancer. This, we believe, could provide a means of detecting breast cancer at an early stage employing a novel biomarker in a very sensitive, non-invasive and inexpensive assay.

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Early Detection of Breast Cancer and its Recurrence

Ashraf Imam, Ph.D.
University of Southern California

Breast cancer is a leading cause of death among women in California (new cases per year: approximately 18,000 and mortality per year: approximately 4,000). With such a large population of women developing breast cancer each year in California, it is important to establish a method of identifying: (a) women with ductal carcinoma in situ (DCIS) -- a localized and noninvasive pre-malignant lesion, usually discovered by mammography --who have a with high risk of subsequently developing invasive breast cancer; and (b) patients who are at a high risk of developing recurrence of their primary breast cancer. Early identification of high-risk patients in these groups is essential in order to develop strategies for prevention and effective therapy.

Although emerging methods to identify high risk groups of women are promising, they are not yet reliable. We have recently identified a biomarker termed LEA.135 which, in a preliminary study of 111 cases of women with primary breast cancer, identified over 80% of the patients (LEA.135-positive) with low risk of developing recurrence and with an increase in overall survival.

The proposed study, in accordance with BCRP's priority to improve early detection of breast cancer, seeks to evaluate the above finding on a large number of cases as described below.

The specific aims of the proposal are as follows:

  1. To further evaluate, by incorporating a larger number of cases (584), the usefulness of LEA.135 as a favorable prognostic biomarker for patients with primary breast cancer.
  2. A significant difference in survival between black and white women with breast cancer has been widely reported in the United States. We propose to conduct a study (100 cases) to determine whether LEA.135 expression provides a useful basis for evaluating the difference in prognosis between black and white patients with primary breast cancer.
  3. A significant number of women patients with initial localized and noninvasive breast ductal carcinomas in situ (DCIS) who have been reported to have high risk of developing invasive breast cancer will be the subject of a study for the expression of LEA.135. The proposed study (200 cases) will determine whether LEA.135 expression is associated with decreased risk of developing invasive breast cancer in this group of patients. An early identification of patients with low vs. high risk will be helpful in determining an appropriate and effective treatment.

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Early Breast Cancer Detection with Fiberoptic-CMOS Detector

Anthony Seibert, Ph.D.
University of California, Davis

This proposal seeks to develop an x-ray detector that can dramatically improve image quality, particularly for those situations where the breast characteristics result in mammograms with poor diagnostic information. Earlier and more sensitive detection of breast cancer can lead to a significant reduction in human and economic costs associated with this disease. When breast cancer is found at an early stage before spreading to other parts of the body, treatment most often consists of a simple surgical removal ("Lumpectomy"), and the patient's outlook for survival is at its best. Presently, x-ray mammography screening is the most efficient method available to detect small breast cancers at the early stages of growth. However, improvements are needed in the detector technology to enhance the quality of the x-ray images so that the radiologist can confidently detect even smaller cancers.

The increased attention that breast cancer has received over the last decade has prompted intense efforts in the development of new machines (digital mammographic systems) capable of producing better x-ray images. In conventional x-ray detectors using a film detector, not all of the incident x-rays are used to make the image. This is because certain parts of the detector must be made very thin to maintain a sharp image. A higher radiation exposure is therefore required to produce a useful image. Also, it is easy to under- or over-expose the film during the procedure, which often requires the procedure to be repeated.

The first phase of this research will investigate a new type of detector called a "fiberoptic scintillator" just recently made available. These detectors have a unique capability of producing light from X rays and channeling the light down a "light-pipe" to an image camera. Even with a thick detector that can capture all of the X rays, the fibers maintain the image detail. Because the fiber detector absorbs nearly all of the X rays, the radiation dose can be lowered in many instances compared to the standard x-ray film procedure. The second phase of this research will investigate a new digital image camera called a "CMOS (Complementary Metal Oxide Semiconductor)-Active Pixel Sensor (APS) photodetector array" that captures the light image and converts it to a digital image that can be displayed on a computer monitor. What is exciting about this device is that large areas can be manufactured, and it is likely to be lower in cost compared to other types of digital cameras. The large area of both the fiber detector and the digital camera will allow a large area direct capture device to be constructed for mammography. In addition, the digital camera has a much larger tolerance for variations in light exposure than does x-ray film, which reduces the need for x-ray retakes. Finally, because the output image is stored in a computer, image processing routines can be developed and applied to the image in order to enhance and improve the detection of breast cancers that might otherwise not be seen by the radiologist.

In summary, this proposal has as its primary goal the development and testing of a "fiberoptic scintillator-CMOS-APS photodetector array" that is better than conventional x-ray mammography detectors. We hope to demonstrate that the proposed fiberoptic-CMOS detector can significantly outperform the detectors used conventionally, such that breast cancers can be detected at an earlier stage of development. Hopefully these results will lead to the earlier availability of the technology from the manufacturers of mammography systems so that all women can receive the benefits of earlier detection.

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High Resolution Breast Gamma Emission Imaging System

Manbir Singh, Ph.D.
University of Southern California

This proposal is directed toward the design and development of a dedicated breast scanner (that is, developed and used with this one purpose in mind) for use in nuclear medicine that would be easier and less costly to use, and more accurate than current gamma ray imaging cameras. (Gamma rays are a kind of X ray.) Although conventional x-ray mammography provides the ability to see detail ("spatial resolution") ranging from .01 to 0.1 millimeters to visualize breast lesions and any structural changes related to anatomy, surgical biopsies are generally required to distinguish benign (non-cancerous) from malignant (cancerous) lesions. However, approximately 400,000 of the 600,000 lesions (also called lumps, masses, or tumors) removed at surgery in the United States each year prove to be benign. An imaging technique to determine whether a lesion is malignant or benign without requiring a biopsy would thus be of great significance to how breast cancer is diagnosed and monitored. If, in fact, it could be established whether a lesion is malignant or benign without requiring a biopsy, the savings, both psychologically and monetarily, would be enormous.

Preliminary studies have shown that non-invasive nuclear medicine imaging techniques, where a pharmaceutical to which a trace amount of radioactivity is attached is introduced into the body usually through an intravenous injection, can allow us to determine biochemical characteristics of a lesion indicating whether it is benign or malignant with an accuracy greater than 95%. Current nuclear medicine studies are conducted either with gamma ray emitting radiopharmceuticals based on a common radioisotope known as Tc-99m, or with specially produced radiopharma-ceuticals that emit energy particles known as positrons. Our idea is that a gamma imaging scanner designed exclusively for the breast could achieve an improvement, by a factor of three, in spatial resolution over current gamma emission imaging systems, thereby yielding significant improvements in the sensitivity (the ability to detect a mass) and specificity (the ability to distinguish benign from cancerous masses) of breast imaging.

Currently, lesions smaller than about 8 millimeters are not seen in conventional nuclear medical scans. The high resolution of the scanner we propose to develop should enable visualization of lesions in the 3-8 millimeter range for the first time, and, at the same time, significantly reduce the incidence of false negatives (that is, failing to detect a mass which is present in the breast), a major concern at the present time.

The scanner relies on a cylindrical design using high-resolution semiconducting detectors which have only recently become practical for applications of this type. We propose to design a system where semiconducting detectors will be tiled on a cylindrical surface to cover a larger portion of the breast. Use of semiconducting detectors instead of currently used scintillation detectors more commonly in use in nuclear medicine will also eliminate a drawback of current scanners which makes it very difficult to image close to the chest wall. With our proposed detectors it will become possible to image very close to the chest wall at the same time avoiding any background radiation from the heart. In addition, the proposed scanner will attain a resolution similar to that attainable with larger, more expensive dedicated positron emission mammography systems, but at a significantly reduced cost for the radiopharmaceuticals.

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DigiMAM: A Sensitive Early Detection System for Breast Cancer

Tumay Tumer, Ph.D.
Nova R&D, Inc.

Mammography has attained widespread acceptance as an important tool for the screening and diagnosis of breast cancer. In traditional mammography, the breast is x-rayed and the X rays transmitted through the breast are detected and recorded by an 'image receptor". Current systems use phosphor screens and photographic film as the receptor. The image is then processed for display on a viewbox. In such film-based mammography, processing of the image is a chemical procedure carried out in a darkroom and there is little flexibility in how the film can be processed. The contrast of the image (which is one factor in determining how well different features within the breast may be seen) on film has a narrow range, which is fixed by the film type and processing conditions (time, temperature and chemical activity). Thus, a particular film image cannot be reprocessed to get a better image, and getting another (better) image requires re-exposure of the patient to X rays. We propose to build prototype solid state pixel detectors as part of a larger system that would replace film (by having the x-ray data go first into a computer in "digital form" which would then generate the image on screen instead of only creating a film image). In addition, we will study the pixel effectiveness for application to digital mammography.

Acquisition of mammograms in digital form offers the possibility of overcoming the limitations of film imaging since, once the image data is in the computer, it can be easily manipulated to obtain the best possible image. In fact, there are several ways in which the performance could be enhanced and the sensitivity of breast cancer detection and diagnosis improved. Such improvements may be in terms of higher contrast, better image resolution (enabling features in the breast to be more easily seen), and the reduction of "noise" (i.e., unwanted electrical signals) in the system. The computer-based images can also be sent through networks for expert consultation.

These improvements will initially come from acquisition of digital images using the more efficient and higher contrast solid state x-ray crystal detector. Detector elements will be laid down on these crystals so that an image of the X rays passing through the patient's breast can be produced. These detectors directly convert x-ray energy into electrons (which are used to form the digital images) and can provide superior images with high resolution and low "noise". These detectors also absorb nearly 100% of the X rays transmitted through the breast, compared to less than 50% for the x-ray films presently used for mammography. This offers the potential for sharper images of the structures in the breast at less than half the radiation dose than currently required. If development of the detectors is successful, we would, using other funding, then line these detectors into a narrow column to scan underneath the patient's breast.

In summary, the improved image resolution and exceptionally good contrast we expect to achieve would result in more accurate images of breast anatomy (using less than half the radiation dose), and therefore more accurate detection of breast cancer.

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A New Radiotracer for Sentinel Node Imaging of Breast Cancer

David Vera, Ph.D.
University of California, Davis

We propose to synthesize and test a new radiopharmaceutical for sentinel node imaging of women with breast cancer. Sentinel node imaging is a nuclear medicine examination which identifies for the surgeon the first lymph node to receive lymphatic flow from the breast tumor site. Because this node will be invaded first by malignant breast cancer cells, its removal and microscopic examination is an extremely sensitive index of metastatic disease (the spread of the original cancer to other parts of the body). By identifying the sentinel node prior to surgery, a small incision can be used to remove the node. Moreover, the examination may rule out the axillary node as the sentinel node. This ability to avoid axillary node dissection decreases morbidity, expense, and permits the patient to return to normal activity much sooner after surgery.

The current sentinel node imaging agent, technetium-99m-antimony-trisulfide colloid, was recently withdrawn from the U.S. market and is therefore only available in Europe, Japan, and Australia, or at highly specialized clinical centers where the agent is prepared on site at great expense. Our new sentinel node imaging agent will be less expensive and safer than technetium-99m-antimony-trisulfide, which was developed in the mid-1970s and consists as very small radiolabeled particles of sulfur. We will employ a new class of radiopharmaceuticals called receptor-binding radiotracers. These imaging agents exist as individual molecules which recognize and bind receptors molecules that reside within the target tissue that we wish to image. Compared to labeled particles, such as [Tc]antimony-trisulfide-colloid, receptor-binding radiopharmaceuticals provide greater quality control during manufacturing of the commercial kit and less time during preparation of the patient's imaging dose. As a result, (99mTc]DTPA-mannosyl-dextran should not only fill the void created by the withdrawal of [Tc]antimony-trisulfide colloid, it should also provide an increase in diagnostic performance at a lower cost.

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Engineered Antibodies for Breast Cancer Imaging and Therapy

Anna Wu, Ph.D.
Beckman Research Institute of the City of Hope

Monoclonal antibodies have been produced that can bind specifically to breast cancer cells. Radioactive materials can be attached to these antibodies to provide a means for targeted delivery directly to the cancer cells - the "magic bullet" concept. Radioisotopes such as indium-111 give off radiation that can be used to detect breast cancer (with radiation-detecting "cameras"), whereas others such as yttrium-90 emit radiation that can kill cancer cells (therapy). A protein called Carcinoembryonic antigen (CEA, found in the majority of breast cancers) is an excellent target for such antibody-directed approaches. Indeed, serum levels of CEA are commonly used in follow-up of breast cancer patients. A long-term goal of our group is to develop and implement radiolabeled anti-CEA antibodies for imaging and therapy of cancer.

Many practical issues must be addressed before monoclonal antibody imaging or therapy become clinically useful. Fortunately, genetic engineering has provided a powerful approach for tailoring the antibodies to have the proper characteristics for use as targeting agents in patients. Previous work has resulted in antibodies that will not provoke an immune reaction in patients which would destroy the antibody before it reached the cancer cells. Engineered antibody fragments have been produced that show rapid, high-level targeting of tumors. We have used molecular engineering to produce a small anti-CEA antibody fragment called the "minibody" which shows excellent tumor targeting in preclinical studies. An additional area for improvement is the final step in readying these antibodies for clinical use: the radiolabeling step. Current labeling methods result in attachment of the label at random sites on the antibody. This process can be inefficient, variable, and frequently inactivates the antibody, making it no longer useful.

In this study we propose to genetically engineer the anti-CEA minibody and to improve the radiolabeling process so that this step is specific, efficient, and does not interfere with the ability of the minibody to bind to breast cancer cells. Genetic engineering will be used to place unique, chemically reactive sites on the minibody. The modified anti-CEA minibodies will be produced, purified, and characterized. Radioactive indium or ytrrium can then be selectively attached to the unique reactive sites in a controlled, reproducible fashion. At the end of the study, site-specifically labeled anti-CEA minibodies will be available for preclinical and eventually clinical studies. Yttrium-90-minibodies are a promising new immunotherapeutic approach for treatment of breast cancer. Indium-111-minibodies can play a very useful role in detection, staging, and/or follow-up in breast cancer patients with CEA-positive tumors.

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Innovative, Developmental and Exploratory Awards (IDEAs)


Non-Invasive Optical Detection of Breast Cancer

Bruce Tromberg, Ph.D.
University of California, Irvine

Pathologists routinely examine thin sections of surgically-removed tissue in order to diagnose cancer. If similar information could be provided by techniques that allow us to see inside the body, physicians could locate tumors non-invasively. Historically, this reasoning led to the development of "breast diaphanography", a near-infrared (NIR) light imaging method introduced nearly 70 years ago to locate and identify breast cancer. NIR imaging is a simple, low-cost, risk-free procedure which, unlike x-ray mammography, does not employ ionizing radiation. Unfortunately, the initial promise of NIR diaphanography was never realized, primarily due to the effect of intense light scattering. Scattering blurs our ability to find small, buried, light-absorbing tumors much in the same way that a cloud obscures our view of an airplane passing overhead.

Distinguishing between absorption and scattering is generally recognized as the principal limitation to detecting breast cancer with light. This problem has puzzled scientists who study how light interacts with highly scattering (turbid) materials for hundreds of years. Recent developments in theory and instrumentation, collectively referred to as "Photon Migration", now enable us to probe and analyze multiply-scattered light signals on an ultra-fast time scale, e.g. a millionth of a millionth of a second. These technological advances provide, for the first time, a simple framework for measuring the exact magnitude of absorption and scattering (i.e. optical properties) in turbid materials. Optical properties can, in turn, be used to locate and identify physiological changes characteristic of tumors. The purpose of this grant is to gather data essential to determining whether NIR breast imaging is truly feasible.

We have been involved in the development of Photon Migration (PM) instrumentation and theory for the past six years. Research by our group and many others in the Biomedical Optics community has rejuvenated interest in optical methods for breast cancer detection. The use of ultra-fast light provides new information with the same advantages as conventional diaphanography (e.g. low cost, zero risk, compact devices). However, in order to demonstrate whether normal and malignant structures can actually be resolved using light, reliable measurements of breast tissue optical properties must be performed in human patients.

Few studies have been completed which accurately measure human tissue optical properties, primarily due to the fact that PM is still an experimental technology. As a result, the essence of the proposed work is to use our specially-designed, portable, hand-held PM probe to measure optical properties in breast cancer patients. This will provide critical information for determining whether non-invasive "optical mammography" is truly feasible. In addition, by measuring unique tumor optical signatures in patients, we expect to gain important insight into physiological changes associated with malignancy, disease progression, and response to therapy.

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Novel Agent For Lymph Node Imaging And Targeted Gene Therapy

Eric Wisner, Ph.D.
University of California, Davis

The primary purpose of this study is to develop a contrast agent that improves detection of cancerous lymph nodes in women with breast cancer. An additional goal is to determine if the same agent can simultaneously be used to transport genetic material to cancer cells as an innovative method of cancer therapy.

Depending on the size of the primary lesion at the time of the initial cancer staging (that is, the determination of the size, nature, and extent of the tumor), up to 65% of women with breast cancer have a cancer that has spread (metastasized) to the lymph nodes in the nearby area of the original cancer. Physical examination and diagnostic imaging procedures (such as X rays) are currently unreliable for determining whether or not the cancer has metastasized to the lymph nodes, and therefore surgical removal of regional lymph nodes is often required for accurate cancer staging. For those patients with cancerous lymph nodes, systemic chemotherapy, radiation therapy and/or surgery is currently necessary for control of regional disease. Although not yet routinely used, many recent studies have shown that incorporating pieces of DNA into cancer cells (gene transfection) can halt tumor growth and sometimes result in shrinkage of the tumor. Developing strategies to improve the efficiency of gene transfection could result in revolutionary changes in the way cancer is treated.

Magnetic resonance imaging (MRI) is one of a number of diagnostic imaging tests currently used to evaluate lymph nodes for cancer staging. However, because lymph nodes appear similar to surrounding tissues on MR images, lymph node detection can be difficult and telling the difference between normal and cancerous nodes is often impossible. Therefore, the development of an easily administered "contrast" agent_a substance that increases the visibility of node tissue -- could significantly improve lymph node detection and cancer staging accuracy.

We intend to develop a new and novel contrast agent by combining a currently used MR contrast agent called Gd-DTPA with microscopic particles known as liposomes. When injected under the skin, this new contrast agent should accumulate in the small lymphatic vessels and be carried to regional lymph nodes. In the targeted node, the agent will collect and concentrate, producing a defined area of contrast enhancement. MR imaging studies will then be performed to determine the extent of enhancement of the lymph node image. Imaging properties of the agent will be evaluated both with and without genetic material (DNA) incorporated into the liposome core. We will then determine the extent of DNA uptake and expression in cells within targeted lymph nodes. Successful transport and incorporation of DNA into lymph node cells using Gd-bound liposomes would demonstrate the potential of this material to serve both as a therapeutic and as a diagnostic imaging agent.

Development of an easily administered contrast medium that enhances regional lymph node appearance on MR images could lead to earlier detection of breast cancer metastasis and more accurate cancer staging. This could also have a significant clinical impact in reducing the need for diagnostic surgical lymph node removal and its attendant complications. Directed gene therapy targeted to regional lymph nodes could also provide an ancillary or alternative approach to current regional breast cancer treatment strategies.

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Postdoctoral Fellowship Award


A New and Practical PET Detector for Imaging Breast Cancer

Yiping Shao, Ph.D.
University of California, Los Angeles

The aim of this project is to develop new imaging detectors which will lead to improvements in the early detection of breast cancer. Currently, mammography is accepted as the best screening tool for breast cancer. A mammogram is obtained by shining a beam of X rays through the breast onto a piece of photographic film. The benefit of mammography is that it produces very detailed images of the breast. However, while it does show many cancers at an early stage, it also often gives results that are interpreted as suspicious for cancer in many women who, in fact, do not have breast cancer. These women must go through the psychological and physical distress of a biopsy test to confirm or reject the possibility of cancer. Less than 30% of mammograms which show suspicious features actually indicate a breast cancer. Thus, the other 70% of women have been subjected to an unnecessary biopsy, and often another mammogram. Another difficulty is that high quality mammograms are difficult to obtain in certain groups of patients, for example, those with silicon breast implants, those who have already had breast surgery, and some young women with particularly dense breasts.

While mammography, because of its low cost and proven ability to detect cancers, must for the present remain the first stage of screening, it would be very useful to have a second, non-invasive test, which could help to reduce the number of unnecessary biopsy procedures and also provide diagnostic information. Positron Emission Tomography (or PET, for short) is one such possible technique. In PET, a minute amount of a radioactively labeled substance is injected into the body through a vein in the arm. This substance would typically be a close relative of glucose, a sugar which is used by cells to provide energy. Because cancer cells are growing and multiplying rapidly, they require more energy than normal cells and therefore will accumulate more of the "radioactive sugar". An image of the radioactivity in the breast can therefore reveal tumors, which will show up as "hot" regions on the image. PET images differ fundamentally from mammograms in that they are providing a measure of how the breast tissue is functioning, not just the anatomy of the breast. Many things can cause the breast anatomy to appear distorted on a mammogram, cysts being one common example, but only tumors will accumulate large amounts of the radioactive sugar, therefore making PET a more specific tool than mammography.

The goal then is to develop high quality and low cost nuclear medicine imaging procedures which can be used as a second stage of screening. This proposal involves the design and development of a new class of nuclear medicine detectors, designed specifically for imaging the breast. Other research groups have already used nuclear medicine procedures to image the breast, but they have either used existing nuclear medicine scanners (which are designed to image the whole body and are therefore bulky and expensive) or have taken existing detector designs and modified them for breast imaging. We believe that better quality images can be achieved at a lower cost by specifically designing detectors for breast imaging, taking into account the unique geometry of the breast from the very start. The individual detectors must then be combined in an intelligent geometry to form a breast camera which produces images with fine detail and contrast, covers the whole breast, images as close to the chest wall as possible, at a cost which makes it readily available to hospitals throughout the country. Our detectors use the latest fiber-optic technology to allow great flexibility and are based on proven technology, so that the designs proposed can be converted into a clinical device in a reasonable time scale. We believe the research in this proposal will form the basis for the design of a high quality nuclear medicine breast camera which we can then proceed to build, in collaboration with industry, in readiness for clinical trials.

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Training Program Award


UCLA Biomedical Physics Graduate Training in Breast Cancer

Carolyn Kimme-Smith, Ph.D.
University of California, Los Angeles

The purpose of this grant is to train graduate students to become research scientists and teachers with knowledge in the diagnosis and treatment of breast cancer by the techniques of radiology and radiation therapy. Currently, UCLA has a graduate program in Biomedical Physics which trains students in the general aspects of radiological techniques and radiation therapy, but there is no emphasis on breast cancer studies.

Scientists in the field of Biomedical Physics, who specialize in breast cancer, develop and study methods for the detection and treatment of breast cancer with ionizing radiation, such as X rays or gamma rays. More recently, these scientists have also been developing the use of non-ionizing radiation to diagnose breast cancer with ultrasound and magnetic resonance imaging techniques. To detect breast cancer with mammography, they have developed special very high resolution x-ray systems that can detect very small breast tumors. Since many cancerous cells are very sensitive to radiation, radiation is frequently used to treat breast cancer tumors. The concepts used to develop radiation therapy for tumors come from a Biomedical Physics subspecialty, radiation biology, which is the study of how radiation affects tumor cells and is very important in the understanding of the treatment of breast cancer. In Nuclear Medicine, the ionizing radiation is associated with radio-isotopes that are attached to molecules that will go to the breast tumors. The location of the tumors are then determined detecting the gamma-rays emitted from the isotope taken up by the tumor.

Currently, there are no Biomedical Physics programs that provide an emphasis on the problems of diagnosing and treating breast cancer. Since there are no organized programs in breast cancer studies at UCLA at the present time, few students in our program are considering breast cancer research projects or training as part of their graduate education. An organized program with funding for their studies would both encourage, and provide the support for, students to specialize in the study breast cancer.

We will select five students who have completed their first year of general core classes in Biomedical Physics, and train them in all aspects of breast cancer detection and treatment as practiced in Radiological Sciences and Radiation Therapy. Each student will select a research topic concerning breast cancer and will write a Ph.D. thesis on this topic. At the conclusion of this training grant, we will have a nucleus of young researchers, who will be able to staff medical schools and hospitals and educate engineers and physicians in the technical aspects of breast cancer detection and treatment, as well as conduct research to develop the breast cancer diagnostics and therapies of the future.

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