Early Detection

Until effective strategies to prevent breast cancer are available, the best defense against dying from the disease are early detection and treatment. Although widespread use of current methods to detect breast cancer (self exam, clinical breast exam and mammography) is thought to be at least in part responsible for recent decreases in the number of deaths from breast cancer, safer, easier and more effective methods to detect cancer are needed. In Cycle III, the BCRP targeted three areas of importance: developing new technological and/or biological means to detect breast cancer; improving current methods of detection, and increasing access to current methods of detection for underserved populations. Grants in all three of these areas were awarded.

Three grants described in this section are focused on developing and testing new methods to detect breast cancer. In the first, a protein that is found in both non-invasive and invasive breast cancers, but not in normal breast cells, is being examined for its potential as a marker of breast cancer (Margaret Huflejt, PI). In the second project, work previously funded by BCRP is being followed up on to test the ability of modified antibodies to detect breast cancer at a very early stage (William Pardridge, PI). In another approach, new compounds that could be used to detect the new blood vessel growth that early tumors stimulate will be synthesized and tested (Michael Samoszuk, PI).

In an effort to improve the interpretation of abnormal mammograms, another investigator is creating a computerized system based on digitized images that compares a mammogram to a large collection of other mammograms with known results (Jack Sklansky, PI). Use of this computerized system is expected to enable radiologists to make more accurate diagnoses, thereby also reducing the number of unnecessary biopsies.

Finally, two funded projects aim to investigate ways to overcome cultural and socioeconomic barriers to screening among underserved populations, including Pacific Islanders (Sora Park Tanjasiri, PI) and the Hmong Community (Mary Anne Foo and Marjorie Kagawa-Singer, co-PIs). Another project designs and tests multiple approaches to increasing repeat annual screening in programs such as the Breast Cancer Early Detection Program (Nicole Howard and Greg Talavera, co-PIs). Two of these projects were pilot CIRC awards, proposed and designed by collaborative teams of community members/agencies and research scientists and intended as precursor awards to provide the basis for a full research award (either as a full CIRC from BCRP, or from another funding agency.)

These projects continue the direction taken in the first two cycles by funding a portfolio of grants that aggressively pursue research leading to safer and more effective techniques for earlier detection, as well as access to, and delivery of, these techniques. In Cycle IV, BCRP will continue this focus on early detection, emphasizing novel technological and biological strategies and de-emphasizing the promotion and further development of x-ray mammography.

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IDEA Awards

Galectin-4 As a New Marker for Breast Cancer

Margaret E. Huflejt, Ph.D.
La Jolla Institute for Allergy and Immunology

The long-term goal of this research is to develop a simple, cost-effective, and broad range screening procedure for the detection of breast cancers using a novel diagnostic marker. In the future, this research could lead to other clinical applications, including treatment.

We have found that a protein called galectin-4 is expressed in non-invasive and invasive breast cancers but not in normal breast cells. The antibody to galectin-4 strongly stained all of the breast cancer tissues we tested, whereas the normal breast cells adjacent to the tumor did not stain. An anti-galectin-4 antibody was able to detect the presence of galectin-4 very specifically. It was possible to detect small nests of tumor cells, or even single tumor cells, in unexpected locations such as fat tissue and among aggregates of tumor associated white blood cells.

The current view in the field of diagnostic surgical pathology is that at least some breast cancers progress through a series of pre-cancerous stages. However, existing methods do not allow for the precise determination of the point at which the pre-cancerous disease becomes cancer. Information about the presence of galectin-4 on a cell might prove extremely useful in helping us to make this distinction. The presence of galectin-4 at an early stage of non-invasive breast disease as well as in invasive cells strongly suggests that this protein is involved in the processes underlying tumor progression. Therefore, in the main project of this research we will investigate the possibility of using galectin-4 as a specific diagnostic marker of breast cancer whose patterns of expression at early stages of disease could identify those patients with a high risk of progression to aggressive cancers. We will use several alternative approaches such as nucleic acid-based probes and immunoblotting to assure correct evaluation of the galectin-4 expression in various types of early breast cancer and in different types of invasive mammary carcinomas. We will also determine whether expression of galectin-4 in presumptive pre-cancer lesions is correlated with the onset of the progression to malignancy.

Our preliminary results show that galectin-4 modulates cellular adhesion. Therefore in the second project we will introduce galectin-4 into cultured "normal" breast epithelial cells that do not express galectin-4 and determine whether this protein can alter the proliferative and migratory properties of breast cells.

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New Imaging Modality for Early Detection of Breast Cancer

William M. Pardridge, M.D.
University of California, Los Angeles

This work is aimed at developing a non-invasive diagnostic test that would allow for the early detection of breast cancer. This new approach will merge three methodologies in the biological sciences: tumor-specific proteins called monoclonal antibodies; x-ray imaging of these antibodies, which are tagged with radioactivity; and a chemical modification of the antibody, called "cationization", which gives the antibody electric charge. The novel feature of the proposed work is the use of "charged" antibodies as imaging 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 to the tumor antigen buried within the breast tumor. This lack of access is due to the fact that antibody proteins are too large in size to escape the blood circulation and do not effectively enter into the cancerous tissue from the blood.

The present application will use a new antibody delivery technology that allows circulating antibodies to rapidly escape from blood to enter the tumor issue. A specific antibody will be used in these studies, and this antibody targets a specific protein that is produced by many breast cancers. After the "cationization" modification of the antibody, it will be tagged with radioactivity. The tumor uptake of the antibody can then be detected by technologies available in standard x-ray clinics, such as single photon emission computed tomography (SPECT).

The present studies will use human breast cancer cells and these cells will be transplanted into experimental animals. The experimental tumors will then be imaged with the new antibody delivery technology. The ability of this technology to detect human breast cancer at the very early stage will be examined and it is hoped that the use of this antibody delivery technology will create a significant advance in the detection of human breast cancer. If these studies give positive results, then an entirely new approach to early detection of breast cancer will have been developed.

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MRI Detection of Breast Cancer Blood Vessels

Michael Samoszuk, M.D.
University of California, Irvine

Angiogenesis (blood vessel growth) plays a critical role in breast cancer progression and metastasis (spread in the body); and could be an important target for early detection and therapeutic intervention. Numerous angiogenesis-associated proteins (vascular endothelial growth factor, basic fibroblast growth factor, pleiotrophin, heregulin, and eosinophil cationic proteins) are detectable in human breast cancers. All of these proteins have extensive basic, positively-charged regions having a high affinity for heparin, a polyanionic glycosaminoglycan that is routinely used to block blood clotting. Therefore, we propose to synthesize, purify, characterize, and test a novel compound, heparin-albumin, that will deliver a contrast agent (GdDTPA) suitable for magnetic resonance imaging (MRI) of the new blood vessels that form within breast cancers. MRI is potentially more sensitive than mammography and can be utilized to detect specific breast cancer components. The proposed studies will involve a multidisciplinary collaboration between a university-based physicist and a pathologist.

In the first phase of this project, we will synthesize the new compound (heparin-albumin GdDTPA) using a well-established chemical procedure. After purification of the compound by sequential chromatography, we will then perform detailed characterizations in the laboratory, including measurement of its heparin content and analysis of its binding to a strong anion resin. In the second phase, we will conduct studies initially in mice bearing a human mammary cancer cell line (MCF-7), and subsequently in rats bearing subcutaneous implants of an adenocarcinoma cell line . We will use immunohistochemistry to study the biodistribution of a derivative of the compound (heparin-albumin GdDTPA) at various times after intravenous injection (12 minutes to 3 hours). The third phase of the project will consist of sequential MRI studies in tumor-bearing mice and rats that will receive intravenous injections of the compound. This mimics the conditions that would be used in women either diagnosed with or suspected of having breast tumors or suspect lesions, such as ductal carcinoma in situ (DCIS).

Our aim is to extend these experiments into a multidisciplinary drug-discovery effort to develop a novel strategy for early detection of breast cancer. The overall advantage of this approach is that it avoids the use of radiation and can detect potentially invasive tumors at an early stage. This approach also has the potential of targeting therapeutic compounds to the site of tumor angiogenesis to block the progression of breast cancer.

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Computer-Aided Diagnosis in Digital Mammography

Jack Sklansky, Eng. Sc. D
Charles R. Drew University of Medicine and Science

We plan to create a computer system that will help radiologists to use large collections of digitized mammograms as aids in determining whether or not to recommend biopsies. Roughly two of every three breast biopsies recommended by a radiologist are unnecessary because they are benign (non-cancerous). The best available means of reducing the number of these unnecessary biopsies is a second opinion from a consulting radiologist. Often such a radiologist is not available or cannot be reached when needed. In these circumstances the proposed computer system will give the radiologist advice that is at least as reliable as that of a second radiologist, and possibly even more reliable. It will also give the radiologist a simple way of finding other mammograms that are medically and visually similar to the one being analyzed. This will enable the radiologist to diagnose mammograms more accurately and eliminate many biopsies of benign breasts. As a result, the proposed diagnostic system will lower the cost of second opinions, eliminate unnecessary surgical procedures, and reduce the degree of psychological stress among patients.

This research is made possible by "digitization" technology, which converts film mammograms into digital electronic data that can be processed by computer. Since about 1990 this technology has become so faithful to the original mammogram, so fast and so inexpensive to store, that several major hospitals have begun building large files of "databases" containing hundreds of digitized mammograms, along with the diagnoses and subsequent medical histories of the patients. Several of these databases have been made available to this project.

This research will be carried out at the Charles R. Drew University of Medicine & Science and the King/Drew Medical Center, the preeminent medical school and hospital in Southern California serving a primarily African-American and Latino community. A major benefit of this study will be the development of a computer-aided diagnostic system attuned to the particular patterns of disease, and the particular mammographic features, of this minority population. In addition, this study will result in improved service to an impoverished and medically underserved community. Further, the means of reducing the costs of unnecessary biopsies will take into account the ways medical costs are paid in this community.

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Postdoctoral Fellowship Award


Breast Cancer Knowledge/Attitudes: California Pacific Islanders

Sora Park Tanjasiri, Dr.P.H.
University of California, Irvine

California represents the major gateway for immigration of Asian and Pacific Islander Americans (APIA) into the United States. While breast cancer remains the most common cancer site for Asian American women, information on the incidence and prevalence among Pacific Islander women is nearly nonexistent. Despite the lack of systematic epidemiological data on Pacific Islander Americans, they possess risk factors for the development of breast cancer. Finally, utilization of breast cancer screening services is predicted to be low among Pacific Islander American women.

This two-year study will attempt to assess and analyze the breast cancer knowledge, attitude and screening behaviors of women aged 40 years and older in two Pacific Islander populations (Tongan and Chamorro, the latter of which are indigenous Guamanians) of Los Angeles, Orange, and San Diego County. Given the dearth of epidemiological and behavioral data on breast cancer among Pacific Islanders, the proposed research will be exploratory in nature. The major research question of the proposed project will be: What are the differences between Tongans and Chamorros in breast cancer knowledge, attitude and screening behavior? What are the predictors (e.g., age, year of immigration, ethnic identity) of Tongan and Chamorro women’s knowledge, attitude and behavior related to screening and breast cancer?

Baseline behavioral data on breast cancer knowledge, attitudes and screening behavior will be collected from a minimum of 600 Tongan and Chamorro women aged 40 years and older. A provider survey will also be conducted in each community to identify culturally relevant providers of breast cancer information and screening services.

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CIRC Awards


Breast Screening Program in the Hmong American Community

Mary Anne Foo, M.P.H.
Orange County Asian and Pacific Islander Health Alliance

Marjorie Kagawa-Singer, Ph.D.
UCLA School of Public Health Department of Community Health Sciences

This preliminary research project targets Hmong American women in California. The study is designed to obtain the information needed to develop a culturally appropriate and acceptable intervention program and materials to enable Hmong women to use early breast cancer screening services.

The full project will develop and test a breast screening intervention program based upon the findings from this proposed pilot study. It is anticipated that by involving the perspective and the voice of the Hmong women and their community leaders from the inception of the design of the project that the design will be more culturally appropriate, acceptable, and effective in promoting breast screening and early detection practices for low-income, Hmong women aged 40 years and older in California.

Asian Pacific Islander Americans (APIAs) comprise the fastest growing minority group in the United States. Hmong Americans comprise one of the major subgroups of Southeast Asians refugees in the U.S. About 60% of Hmong live in California and comprise one of the most disadvantaged groups in the APIA population due to their social history in Laos as well as their experiences here in the U.S. The Hmong number about 46,892, but community leaders estimate the number to be around 60,000.

Currently, no Hmong women in the Long Beach community are known to have obtained a mammogram. Recently, however, a few Hmong women in the community have died from breast cancer, and the community has expressed a need for education and service to help them understand this condition and what can possibly be done to reduce mortality from this disease.

The proposed project is the first effort to study the knowledge, attitudes, cultural beliefs, and screening practices of Hmong women about breast cancer. Two hundred Hmong women in Long Beach (100), Fresno (50) and San Diego (50) will be interviewed. This will be the first study to document individual, cultural, and structural barriers to breast cancer screening among these women, and this information will provide a more informed basis and a joint community collaboration upon which to build breast screening education and service programs for this population of women.

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Increasing Annual Recall in State Early Detection Programs

Nicole A. Howard
CHG Foundation

Gregory A. Talavera, M.D., M.P.H.
San Diego State University

This project seeks to increase compliance with annual recall for breast cancer screening (mammography and clinical breast examination) among low income, uninsured women ages 50 and above, participating in the Breast Cancer Early Detection Program (BCEDP) and the Breast and Cervical Cancer Control Program (BCCCP). The purpose of this research is to test the effectiveness of behavioral strategies designed to increase annual recall rates for BCEDP/BCCCP clients in San Diego and Imperial Counties, who were found to be asymptomatic for breast cancer during their initial or previous screening cycle.

The BCEDP/BCCCP provides free breast cancer screening services to program eligible women on an annual basis. Research has demonstrated that mortality can be reduced up to 30% among women 50 years of age and older through the use of annual screening mammography and clinical breast examination. Currently, more than 5,000 women are being served each month by the state funded programs, with approximately 450-550 women screened per month in the San Diego-Imperial county region. The BCEDP/BCCCP has been extremely successful in providing initial screening services. However, evidence suggests that the program’s underserved target population may not adhere to recommended annual screening over time. With 80,000 women screened statewide since 1991, the BCCCP has only been able to achieve an 18% mammography rescreening rate. The BCEDP/BCCCP is typical of efforts to increase breast cancer screening, "Overall mammography rates have increased substantially in the past decade, but rates of repeat and annual screenings remain low for women in the target age group" (Mayer, 1994). Only with annual screening is breast cancer mortality impacted, by enabling women to benefit from early detection.

This project seeks to: (l) conduct a literature review of cost effective strategies that show promise for increasing annual recall compliance among the target population; (2) through a physician survey and medical record review, identify existing annual recall strategies currently utilized by San Diego-Imperial County primary care providers and determine if new strategies can be incorporated into clinical practice; (3) through discussion groups with women over 50 years of age, ensure that new strategies are culturally sensitive and appropriate; (4) community collaborators will select up to three strategies to be put into place at BCEDP/BCCCP clinics; (5) community partners together with researchers and project staff will evaluate the effectiveness of the three strategies in a small study during Cycle III and in a full scale study in Cycle IV and; (6) send study results to approximately 1,000 BCEDP/BCCCP providers in California in an attempt to retain women in the statewide program over time so that older, low income women at highest risk are diagnosed earlier, possibly leading to better prognosis and a lowering of the number of deaths due to breast cancer.

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