Earlier Detection: Improving Chances for a Cure

As more California women have regular mammograms, examine their own breasts and receive breast exams from their physicians, breast cancer is being detected at earlier stages more often. Earlier detection combined with improvements in treatment has led to a 25% drop in the rate of death from breast cancer in the state.

However there's still room for improvement. Women need detection methods that can find smaller tumors and distinguish harmless breast abnormalities from cancer. Mammograms don't provide information about how aggressive a tumor is, or other diagnostic information. Areas of research BCRP funds include.

Developing and Improving Imaging Technologies. Technologies such as Magnetic Resonance Imaging (MRI) or optical detection hold promise for finding tumors faster and more easily. We have also funded projects to improve the accuracy of the x-ray technology used for mammograms.

Research Conclusions

Developing and Improving ImagingTechnologies

Hybrid Grid-Detector to Improve Early Detection Imaging

John Boone Ph.D., of the University of California, Davis studied a hybrid grid detector system (HGDS) that might be suitable for digital mammography. He attempted to improve the screen that converts X-rays to visible light (which produces the image) and to reduce the X-rays that "scatter" out of the breast and degrade the film image. While he successfully designed and acquired the screen material and a leaded-glass matrix to hold it, he couldn't combine the two components to realize the design goals. However, the components were superior to current mammogram devices. He developed several important tools, including accurate x-ray spectral models and other mathematical techniques for measuring the radiation dose to breast gland tissue during a mammogram.

Computer simulations also demonstrated that the HGDS may be capable of producing twice the light output for the same amount of x-rays. This would improve accuracy of the image. Numerous publications resulted from this project, including Physics in Medicine and Biology 43:2569-82 (1998).

Early Breast Cancer Detection with Fiberoptic-CMOS Detector

J. Anthony Seibert, Ph.D., at the University of California, Davis completed a project to improve digital mammography. He evaluated the use of a new, potentially very low-cost, digital (CMOS) X-ray detector, and combined it with devices called fiberoptic scintillators that could detect x-rays with high efficiency. The fiberoptic scintillators were too inefficient at converting x-rays to light. He substituted an alternative (CsI) scintillator , but because of electronic problems with the CMOS detector, the image quality wasn't good enough to recommend its use in digital mammography. However, he developed several important tools, including a novel method to increase the accuracy of the electronic image of the breast. Published results from this study included Medical Physics 24:279-85 (1997).

Harnessing Technology to Improve Mammography Effectiveness

Laura Esserman, M.D., M.B.A., of the University of California, San Francisco- Mt. Zion Breast Care Center investigated ways to achieve high-quality mammogram screening in California for the least possible cost. When a mammogram shows something abnormal in the breast, the next step is a biopsy, where a tissue sample is taken with a needle or surgery. In the U.S., biopsies reveal cancer at a lower rate than in Europe. Dr. Esserman found this was not because physicians interpreting the mammograms in Europe were missing more cancers, but because physicians there were better at identifying cancers. The more mammograms a physician interpreted, the more likely she or he was to find the cancers that were present and less likely to falsely identify a feature as cancer. Therefore, centralizing mammogram screening so that physicians interpret a high volume of mammograms would improve detection services. Digital mammography could play a major role in this, because computer images of breasts could be transmitted like e-mails from a wide range of locations to a central site where they could be interpreted. Unfortunately, the technology to transmit electronic breast images has not progressed to the extent anticipated at the study's outset. However, Dr. Esserman and her team created a cost model for mammogram screening in the US. They identified the variables that most affect cost and efficiency, along with organizational changes that might save hundreds of millions of dollars, increase cancer detection, and decrease biopsy rates.

Sentinel Node Detection via Targeted Fluorescence

Each breast tumor at first drains its lymph through a single lymph node, the sentinel node. But dozens of armpit nodes serve the breast. At present, they are often all removed to find out if cancer is likely to have spread. However, by finding and removing just the sentinel node, women may be spared the pain and side-effects of having a large portion of the lymph nodes under their arm removed. The challenge is to find the sentinel node. To make this easier, David Vera, Ph.D., of the University of California, San Diego synthesized a molecule that consisted of (1) a glucose chain, (2) a molecule called DTPA radioactively labeled with technetium-99, (3) another chemical, mannose, that binds avidly to lymph nodes and (4) a fluorescent agent, fluorescein. Attaching a radioactive label allows the molecule to be detected in the body with a specialized camera; attaching the fluorescent agent allows it to be detected with light. Having two ways to detect the compound increases the probability of being able to find it in the body. Mannose should make the lymph nodes take up more of the molecule than other surrounding tissues. Dr. Vera is now ready to test the molecule by injecting it into animal tumors to see if it can be used to find a tumor's sentinel lymph node.

Improving Women's Access to Screening

Benign Breast Disease, Biopsy & Cancer Preventive Self-Care

Jacqueline O'Connor, Ph.D., of the University of California, Davis investigated psychological characteristics that motivate women to get mammograms, examine their own breasts and get breast exams from health care practitioners. She also studied variables that predict whether a woman is likely to stop these early detection practices after a breast cancer scare, such as a mammogram that looks like possible cancer followed by a biopsy that reveals no cancer. She found that younger women consider routine breast cancer screening and diagnostic experiences to be more stressful, on average, than do older women. Perhaps this is due to heightened awareness about the issue. Even among study participants with no history of breast problems, younger women reported feeling more at risk and vulnerable to developing breast cancer, on average, than did older women. This was true even though they knew that breast cancer risk increases with age. Women who have experienced a false-positive mammogram or have had a breast biopsy report greater anxiety about breast cancer and heightened perc eptions of personal vulnerability than women who have had only routine screenings with normal outcomes. These feelings may last for more than a year. Finally, even though they feel more vulnerable and anxious, women who have had a breast cancer scare generally don't stop performing breast self exams, or stop obtaining mammograms or clinical breast exams. Results from this funding were published in the American Journal of Roentgenology 171:55-8 (1998).

Improving Access to Mammography in an Urban Underserved Area

Bruce Allen, Jr., Dr. P.H., of the Charles R. Drew University of Medicine and Science, Los Angeles collaborated with researchers at the UCLA-Jonsson Comprehensive Cancer Center. They investigated how to increase the use of screening mammography among African-American and Latino women in a low-income area of Los Angeles. African American and Latino women are diagnosed more frequently with advanced stages of breast cancer. Detecting the disease earlier by raising the rate at which they get mammograms is considered to be an achievable way to reduce their death rate. A baseline survey found that 61% of these African-American and Latino women had had a screening mammogram in the last 24 months, which is lower than the estimate for the general population (71.3%). The survey found that inconvenience, cost, and difficulty in getting to a clinic or office are still barriers to screening. The survey also found that health practitioners can influence whether a woman has a mammogram by providing accurate information in a sensitive manner. Women who had never had a mammogram were more likely to fear breast cancer and radiation exposure, and to be concerned about inconvenience of screening. A short telephone interview resulted in an 8.3% increase in the number of women getting a mammogram, but this was not statistically significant.

Breast Cancer Screening Among Hmong In California

Marjorie Kagawa-Singer, Ph.D., of the University of California, Los Angeles and Mary Ann Foo, MPH, of the Orange County Asian and Pacific Islander Health Alliance, Garden Grove conducted a pilot study in preparation for a larger intervention study. They found that 51% of Hmong women they surveyed had ever performed a breast self-examination, and 54% had ever had a clinical breast exam. Only 27% had ever had a mammogram. These results underscored the need to increase screening in the 60% of the U.S. Hmong population who live in California. The team is now developing and testing an intervention to increase screening in this population with a new BCRP grant.

Novel Screening Approaches

TIMP-3, an Early Indicator of Breast Cancer?

TIMP-3 (Tissue inhibitor of metalloproteinases-3) is a protein that helps to prevent enzymes from destroying tissues. Susan Hawkes, Ph.D., of the University of California, San Francisco developed an antibody that specifically identified TIMP-3. She tested whether the presence of TIMP-3 was associated with more aggressive cancer cells in culture. She found that TIMP-3 was present at low levels in early stage cancer and undetectable in late stage cancer. In the body, it was not detectable in normal or benign tissues, but it was detectable in all pre-cancers (DCIS) and half of the invasive cancers tested. The study provides preliminary evidence that TIMP-3 is an early indicator of breast cancer.

Galectin-4 as a New Marker for Breast Cancer

Galectin-4 is a protein found at high levels in pre-cancerous and invasive breast cancer cells, but not in normal cells. Margaret Huflejt, Ph.D., of the La Jolla Institute for Allergy and Immunology examined over 200 breast cancer tissues and tissues from 70 benign disease cases for the presence of galectin-4. She found that 100% of the early cancers (in situ carcinomas) and 97% of the invasive cancer showed an abundance of galectin-4. In ten of the cases of benign disease, the patients developed invasive cancers within 1-4 years. All ten had "hot spots" of galectin-4 in their benign disease tissues. Dr. Huflejt plans to extend this observation using a larger sample size. Galectin-4 is a promising early biomarker for breast cancer, and it also could help to identify patients at high risk of developing the disease. Dr. Huflejt used this support to contribute as a co-author to a publication in Cancer Research 60:2584-8 (2000).

Identification of Novel Secreted Proteins of Breast Cancer

H. Phillip Koeffler, M.D., from Cedars-Sinai Medical Center, Los Angeles identified a breast cancer gene, called Cyr61. This gene produces a Cyr61 protein that breast cancer cells secrete. Once secreted, the Cyr61 protein helps the cells attach to nearby cells, migrate and form blood vessels that nourish the tumor. Dr. Koeffler showed that estrogen induced the Cry61 protein into two breast cancer cell lines, and that treatment with the drug tamoxifen kept it out. When he introduced the Cyr61 gene into cells, they grew and stimulated blood vessel growth in a manner like that of more aggressive cancers. This research topic is of high interest, because finding proteins that breast cancer cells secrete could lead to a blood test to detect the disease. It could also lead to a treatment that blocks only the specific protein and would not affect normal cells, so it would possibly have fewer side effects. A publication describing these findings was recently accepted by The Journal of Biological Chemistry.

New Imaging Modality for Early Detection of Breast Cancer

Monoclonal antibodies (MAbs) that bond with a single protein found on breast cancer cells can be made in the laboratory. They could be tagged with radioactivity and used for early detection using standard scanning techniques, if only they could reach the tumor in sufficient quantity. William Pardridge, M.D., at the University of California, Los Angeles- School of Medicine attempted to increase the ability of MAbs to cross the blood-tumor barrier, the tiny capillary vessels supplying blood to the breast tumor. He first altered the surface electrical charge of the antibody ("cationization") to determine if this would enable it to cross the blood tumor barrier, and then set out to "tag" the cationized antibody with radioactivity and see if it could still cross. Since human breast cancers often have high levels of a protein called the epidermal growth factor receptor (EGFR), Dr. Pardridge mass-produced a highly promising MAb that binds with the EGFR, cationized it, and tested it to show that the altered MAb retained its structural integrity. He showed that the cationized MAb maintained its active binding to the human EGFR. He also established a method for attaching radioactive 111-Indium to the cationized Mab using a binding molecule called DTPA. He used these approaches to produce images of experimental breast cancers in animals. Results have been published in the Journal of Pharmacology and Experimental Therapeutics 286:548-54 (1998).

Development of EGFR-based Imaging Agents for Breast Cancer

Henry VanBrocklin, Ph.D. of the Lawrence Berkeley National Laboratory, Berkeley is attempting to develop new, radioactively-labeled pharmaceuticals that can be used with nuclear medicine imaging methods to detect epidermal growth factor receptors (EGFR) in breast cancer.

The EGFR are membrane proteins found at the surface of breast tumor cells which, when stimulated, initiate a cascade of cellular events that leads to tumor growth. Dr. VanBrocklin studied five new compounds. Three of them were found to target the EGFR and did not bind similar proteins. Thus, they are promising candidates for imaging breast cancer. He plans to continue to screen new compounds, using many of the techniques perfected in this project, to find an optimal radioactively-labeled pharmaceutical to detect the EGFR in breast cancer.

Research in Progress

Developing and Improving Imaging Technologies

Improving Women's Access to Screening

Novel Screening Approaches

Biomarkers are genes or proteins found in tumors. They can be used to predict how fast tumors will grow or determine what medication will work best against a particular tumor. Two research projects focused on new biomarkers and screening approaches for breast cancer.

Research Initiated in 2000

Novel Screening Approaches

Two investigators will search for ways to detect cancer-related proteins in body fluids.