Earlier Detection: Improving Chances for a Cure

The effectiveness of screening mammography has recently come under question and is being debated in both the lay and scientific press. However, the underlying rationale behind detecting cancers at an earlier stage of progression is strong. 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. 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 a lot of improvement. Women need detection methods that can find smaller tumors and distinguish harmless breast abnormalities from cancer. Mammograms don't provide diagnostic information, such as tumor aggression.

Areas of research the CBCRP funds include:

Research Conclusions

Novel Screening Approaches

Radiographic Densities and Breast Cancer Prevention

When a white woman's mammogram shows a lot of dense tissue, it means she's at higher risk for breast cancer. However, little research has been done about whether this is also true for African American and Asian American women. Malcolm C. Pike, Ph.D., at the University of Southern California, Los Angeles, compared breast density in mammograms of 1,203 white, African American and Asian American women, 706 of whom had breast cancer. Asian American women had the highest percentage of dense breast areas and African American women the lowest. However, the risk of getting breast cancer was not the same for women with dense breasts from the three ethnic groups. The research team compared women with dense breasts (60% or more of the breast tissue appeared dense on the mammogram) with women with low-density breasts (10% or less tissue appeared dense on the mammogram). White women with dense breasts had a breast cancer rate 3.7 times that of white women with low-density breasts. For Asian American women with dense breasts, the breast cancer rate was 2.3 times higher than for Asian American women with low-density breasts. For African American women, dense breasts led to a rate of breast cancer only 1.7 times that of African American women with low density breasts.

Protease Fingerprinting to Diagnose Breast Cancer

Breast cancer cells secrete proteins called proteases that break down other proteins and allow the cells to move. These proteases are also part of the process cancer cells use to recruit the body's blood vessels in order to grow. If there were a way to detect these proteases in blood, it could be the basis for a test that could detect tumors or predict whether a tumor is likely to spread. Jeffrey Smith, Ph.D., at The Burnham Institute, La Jolla, explored a new technology—substrate phage display—to investigate MMP-2 and MMP-9, two proteases known to be involved in breast cancer's spread in the body. He showed that the technology is sensitive enough to detect the proteases. Dr. Smith also gained valuable information about the structure of the proteins that the proteases are able to break down as markers for the presence and activity of tumor proteases. Dr. Smith is collaborating with another CBCRP-funded investigator, Dr. Benjamin Cravatt from The Scripps Research Institute. Results from this project were published in Analytical Biochemistry 294:176-184 (2001) and the Journal of Biological Chemistry 276: 20572-20578 (2001).

Research in Progress

Developing and Improving Imaging Technologies

Non-Invasive Optical Characterization of Breast Physiology.

Bruce Tromberg, Ph.D., from the University of California, Irvine, is making excellent progress on developing a Laser Breast Scanner, which uses harmless near-infrared light to create an image of water, fat, and blood making up breast tissue. The ability to measure concentrations of blood is important, since this could indicate the presence of unusual blood vessel structures that would be expected in tumors that have acquired the ability to recruit their own blood supply. Dr. Tromberg's approach is non-invasive, and compared to mammography, appears to work well for younger women. The hand-held scanner is slightly larger than an ultrasound device; in the future it could be available at low cost in many doctors' offices. Results from this project have been published in Proceedings National Academy of Sciences, USA (2001) 98:4420-5 and Academic Radiology (2001) 8:211-8. Dr. Tromberg is collaborating with Randall Holcombe, M.D. and John Butler, M.D., also from the University of California, Irvine.

UCLA Biomedical Physics Graduate Training in Breast Cancer

Virgil Cooper, Ph.D., of the University of California, Los Angeles, is training graduate students to design and improve early detection and diagnostic imaging equipment, and to solve problems involving these technologies. The training emphasizes awareness of the needs of clinicians and patients. During the second year, five students have been in training. Among the projects on which they have worked are quality control for digital mammography, breast ultrasound, breast density prediction, and reduced compression of the breast in mammography.

Improving Women's Access to Screening

Increasing Breast Health Access for Women with Disabilities

Mary E. Smith, M.S., C.R.C., of the Alta Bates Foundation, Berkeley, Ann Cupolo Freeman, M.S., C.R.C., of the Alta Bates Medical Center, Berkeley, and Carol N. D'Onofrio, Ph.D., of the Northern California Cancer Center, Union City, are investigating problems women with disabilities face with getting breast health services. Using data from a 1994 study, the National Health Interview Survey, they have found that the odds of a woman having had a mammogram within the recommended time period for her age group go down the more physical limitations she has. African American women with disabilities are more likely to be up-to-date with mammograms than white women with disabilities. The team is analyzing data from their own local survey and completing a manual to encourage community organizations to take action to improve disabled women's access to mammograms and other breast health services.

Does Mobile Mammography Increase Screening in Older Women?

Many older women don't get mammograms to check for breast cancer, despite expert consensus that they should. David B. Reuben, M.D., and Roshan Bastani, Ph.D., of the University of California, Los Angeles, recruited women age 60-84 from community sites where older people gather. The team provided health education that included the benefits of mammograms to 247 women; 254 received the health education along with access to a mammogram van at the community site. On-site mammograms resulted in more women having a mammogram than health education alone, especially among older African American, Hispanic, Asian, and Pacific Islander women. The team is now analyzing their data to discover characteristics that predict whether or not older women will get mammograms, and calculating the number of women who would need to have one at each site to make it cost-effective.

Novel Screening Approaches

Profiling of Tyrosine Phosphatases in Breast Cancer

Many of the processes that allow cancer cells to multiply and spread are controlled through a type of reversible chemical reaction among proteins in the cell. The chemical reaction either adds or subtracts a molecule of phosphorus to the protein. These cellular processes are also involved in breast cancer acquiring resistance to drug treatments like tamoxifen. Enzymes called tyrosine kinases add a phosphorus molecule to a protein and tyrosine phosphatases remove one. The balance between these two sets of enzymes controls the fate of the cell. Clifford Tepper, Ph.D., at the University of California, Davis, used a novel method that allowed his team to examine all the tyrosine phosphatases in a cell, combined with another technique that allowed them to examine at the same time 12,500 genes. The information gives a detailed fingerprint of a tumor and allowed the team to discover phosphatases that appear at unusual levels in certain types of breast cancers or in response to certain therapies. The most exciting discovery was a novel tyrosine phosphatase that was not found in two breast cancer cell lines that had higher levels of the HER2 protein. Higher levels of HER2 indicate that the cancer is more likely to be fatal, and also that its growth can be slowed with the drug Herceptin. This tyrosine phosphatase could potentially serve as an indicator of whether Herceptin therapy would be effective. The team also found five tyrosine phosphatases affected by levels of estrogen in cells. One of them, DUSP1, increases 3.5-fold when estrogen is withdrawn from cells. DUSP1 inhibits pre-programmed cell death. Tamoxifen therapy induces cell death by activating a kinase that DUSP1 inactivates. Increases in levels of DUSP1 in cells could lead to tamoxifen resistance.

Molecular Staging of Breast Cancer Progression

Cheng-Ming Chuong, M.D., Ph.D., of the University of Southern California, Los Angeles, is looking for new ways to accurately diagnose breast cancer and predict whether it is likely to spread. Biological researchers are working to develop a set of molecular signatures that can help predict whether a tumor is likely to grow fast, spread, and also whether it can be stopped by various treatments. Microarray technology is likely to be useful to analyze the tumor's RNA. However, current technology requires a large amount of tissue, 20 mg., for RNA analysis. Dr. Chuong recently developed, and is now refining, a technology called RNA-polymerase chain reaction technology that will allow analysis of the RNA of a very small tissue sample. So far, the technology is accurate for a sample of 500 cells, and they hope to increase the sensitivity to be able to analyze single cells.

Clinical Utility of Breast Cancer DNA Markers in Plasma

David Hoon, Ph.D., of the John Wayne Cancer Institute, Santa Monica, is trying to determine whether DNA specific to breast cancer can be detected in the blood. The team has blood and tumor tissue samples from over 270 women. They have isolated DNA from the blood and tumors and are now searching for DNA markers -parts of the DNA that are specific to the tumors-and comparing DNA markers in the blood and tumors. So far, they have developed an array of genetic markers frequently found in breast tumors and have demonstrated that these circulating genetic marker alterations correlate with those occurring in the patient's tumors, and thus may be useful as surrogate markers of breast cancer disease. The number of markers rises as the disease progresses, and the markers in the blood are similar to those in the tumors. The findings of this study will hopefully aid in earlier identification of disease recurrence and help in staging disease to allow early disease intervention which should improve survival.

Research Initiated in 2001

Developing and Improving Imaging Technologies

Novel Screening Approaches: