Earlier Detection: Improving Chances for a Cure

Both the mainstream media and research scientists have raised questions about the effectiveness of screening mammography. 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 detected more frequently 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 information about whether a tumor is likely to grow quickly or respond to a particular treatment.

Areas of research that the CBCRP funds include:

Research Conclusions

Developing and Improving Imaging Technolgies

Measurement of Breast Tissue Viscoelasticity Using MRI.

Michael Buonocore, Ph.D., of the University of California, Davis, is adapting Magnetic Resonance Imaging (MRI) to detect breast abnormalities based on differences in the elasticity and viscosity (thickness) of abnormal breast tissue as compared to normal breast tissue. These same mechanical properties enable a health care professional to detect a lump during a clinical examination. Dr. Buonocore has developed the necessary equipment, including the MRI breast coil with a built-in device to generate mechanical waves in breast tissue, gel phantoms, and image reconstruction software. He has tested the method and confirmed that the images are consistent and repeatable. Next, he will test the adapted MRI in human subjects and develop methods for calculating tissue viscoelasticity from the images. Developing this new technology could lead to earlier detection of breast cancer and may also provide data that could improve the accuracy of manual breast exams.

Improved Access to Screening

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. Older women who had access to on-site mammograms were more likely to have one; 55% of this group had a mammogram within three months, compared to 40% of the group who received health education alone. Onsite mammography appears to be especially effective with two groups of women. Among Latina older women, 56% of women who had access to mobile mammograms had one, compared to 35% of those who received only health education. Among Asian and Pacific Islander women, the figures were 70% versus 35%. These findings indicate that mobile mammography does increase breast cancer screening in older women. An article based on this research has been accepted in the American Journal of Roentgenology.

Novel Screening Approaches

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 want to understand the molecule-level changes—involving genes and the proteins those genes produce—that occur in cells during different stages of breast cancer. Since tumor cells grow near normal cells, it is impossible with current technology to analyze a pure tumor cell sample. Dr. Chuong's team has developed a method that needs only 100 cells instead of the million cells necessary with other methods. It uses technologies called gene amplification and microarray to provide a snapshot of the genes that were producing proteins at the moment the cells were collected. With CBCRP funding, the team refined the method and showed that it works in cells grown in lab cultures. Next, they will test the method in tissue samples. The goal is a kit that can be used in any hospital to find out how far a breast tumor has advanced in its growth and whether it is likely to spread.

Oncogenes, Progression, and Biomarkers.

Robert Cardiff, M.D., Ph.D., of the University of California, Davis, searched for biomarkers. Biomarkers are characteristics for which breast cells could be tested, with the test yielding information about whether the cells were becoming cancerous, already were cancerous, or were cancerous and likely to spread to other body parts. Dr. Cardiff's hypothesis was that genes that control a breast cell's transition from a normal to a cancerous state produce patterns of proteins that could be used as biomarkers. Using antibodies to probe tumors in geneticallyengineered mice, the research team identified several potential biomarkers. One is the protein osteopontin, which is found at very high levels in most tumors but at low levels in healthy tissues. The research team found that the presence of osteopontin may indicate that breast tumors have the ability to spread to other body parts. Dr. Cardiff further found that defects in different genes that are part of the same developmental process within cells result in tumors that resemble each other. Defects in a series of genes known as the Wnt pathway, which are involved in organ development, form tumors with branching shapes. Defects in another series of genes, the erbB2 pathway, which are involved in specialization of cells within the breast, form round tumors with small lobes. This research has led to a better understanding of how cancer genes affect the appearance and biology of tumors, and is a step toward the goal of providing information about a tumor that can predict how it will respond to various possible treatments.

Research in Progress

Developing and Improving Imaging Technologies

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 medically significant problems involving these technologies. The training emphasizes awareness of the needs of clinicians and patients. This year, one student has been trained, working on improving digital mammography.

Non-Invasive Optical Characterization of Breast Physiology.

Bruce Tromberg, Ph.D., Randall Holcombe, M.D., and John Butler, M.D., from the University of California, Irvine, are making excellent progress on developing a Laser Breast Scanner. The portable hand-held scanner uses harmless near-infrared light to measure physical characteristics of breast tissue, such as water content, cell shape, blood volume, and the interaction of oxygen and a component of blood, hemoglobin. In the past year, the team tested the device on two breast cancer patients. The scanner detected changes in the breast tissue of a woman whose tumor was responding to chemotherapy. For another woman whose tumor did not respond to chemotherapy, the scanner showed no changes of the type found in the first woman's tumor. During the coming year, the team will test the scanner on a larger group of women at the University of California, San Francisco. Results from this project have been published in J Biomed Opt. 7(1):60-71 (2002).

Breast CT for Much Earlier Detection of Breast Cancer.

Researchers estimate that a woman's first breast tumor exists for about eight years before a mammogram can detect it. A more accurate and sensitive detection method would reduce this latent period and offer better odds at beating the disease. John M. Boone, Ph.D., and Karen K. Lindfors, M.D., at the University of California, Davis, are building a prototype computed tomography (CT) breast scanner. CT, also known as “CAT scan,” uses special x-ray equipment to obtain image data from different angles around the body. Computer processing is then used to show a cross-section of body tissues and organs. Dr. Boone and colleagues believe their method could detect cancers in the 3-5 mm range. Other advantages include a lack of breast compression and a modest reduction in radiation dose. The rationale for this research was published in Radiology 221:657- 67 (2001).

Patient-individualized Chemotherapy in Breast Cancer.

Daniel H. Silverman, M.D., Ph.D., at the University of California, Los Angeles, is working on a novel strategy to develop a test that would show, in advance, if a particular chemotherapy will eliminate an individual breast cancer patient's tumor. The research team is using chemotherapy drugs that are chemically combined with fluorine-18 (F-18). The F-18 “lights up” when the tissue is tested with positron emission tomography (PET), to detect whether the tumor is taking up the drug. Dr. Silverman is making rapid advances, because he is collaborating with a group that has solved the difficult step of chemically combining F-18 with the drug paclitaxel. This drug is used for advanced breast cancer and in settings where previous chemotherapy has failed. Dr. Silverman's lab is now studying the distribution of F-18 paclitaxel in mice, and is in a better position to develop other F-18-labeled drugs for comparative studies. Although routine use of PET is expensive, this approach could spare women the exposure to chemotherapy that has no chance of working.

Novel Screening Approaches

Protein Markers in Nipple Aspirates for Breast Cancer.

Helena Chang, M.D., Ph.D., at the University of California, Los Angeles, is using a new technology to compare the proteins in fluid from the nipples of women who have had breast cancer with those from women who haven't. The technology (Surface-Enhanced Laser Desorption/Ionization, or SELDI) is a method for rapidly detecting many molecules present in a substance. The advantage of using this technology is that it can detect changes in many proteins at once, whereas conventional technology had restricted researchers to examining a few proteins at a time. So far, the method can determine whether breast fluid is from a normal or cancerous breast. The research team has found one protein that is more abundant in normal breast fluid and another that is more abundant in cancerous breast fluid. This research could lead to an early test for breast cancer based on analyzing a very small amount of fluid obtained from the nipple. If the amounts of various proteins in nipple fluid turn out to be correlated with how tumors respond to various types of chemotherapy, then the potential test could also help physicians select an appropriate treatment.

LPC As a Potential Tumor Marker for Recurrent Breast Cancer.

There are no reliable blood tests to detect recurrence of breast cancer. Two available tests are not accurate enough to be useful. Helen K. Chew, Ph.D., at the University of California, Davis, will test whether measuring the level of a fat found in the blood, lysophosphatidlycholine, or LPC, can be used to detect breast cancer. The research team is also investigating whether LPC blood levels can detect a recurrence of the disease, or reveal whether treatment is working against breast cancer that has spread to other body parts. They are collecting blood samples from 74 women and plan to enroll a total of 91 women.

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 found that DNA markers are frequently present in the blood of women with breast cancer. The number of markers rises as the disease progresses, and the markers in the blood are similar to those in the tumors. The team has also found DNA markers in the bone marrow of early stage breast cancer patients. They are now developing a more efficient method for testing blood for levels of multiple DNA markers. This study could lead to a blood test that could be used for diagnosis, provide information about whether a tumor has spread, or detect a recurrence well before a woman has any symptoms.

Early Detection of Breast Cancer and Its Recurrence.

Cancer treatment specialists need reliable tests that can be done on tumor cells to predict whether the tumor is likely to recur and whether chemotherapy or radiation will be effective against it. Syed Ashraf Imam, Ph.D., of Huntington Medical Research Institute, Pasadena, is investigating whether measuring the amount of LEA.135, a protein found on the surface of some breast tumor cells, can predict whether the tumor will recur and which treatment will be most effective. The team has developed a method for measuring LEA.135 and used it to test tissue samples from biopsies of 480 patients, analyzing the protein levels found on both tumor cells and normal breast cells. They are now evaluating their data.

Research Initiated in 2002

New Imager to Improve Specificity in Breast Cancer Detection.

Kai Vetter, Ph.D., and Christine Hartmann-Siantar, Ph.D., at Lawrence Livermore National Laboratory, are collaborating with Gerald DeNardo, M.D., at University of California, Davis, to build a new type of breast cancer detection system. The system will use gamma rays to detect tumors as small as one millimeter. A woman getting this test would be injected with a drug or antibody that attaches only to cancer cells. This drug or antibody would be tagged with a radioisotope, a chemical that emits gamma rays visible to the detector.

Compositional Breast Density as a Risk Factor.

John A. Shepherd, Ph.D. and Steven R. Cummings, M.D., at the University of California, San Francisco, are collaborating with Karla Kerlikowske, Ph.D., at the Veterans Affairs Medical Center, San Francisco, to use novel x-ray approaches to study breast density. On mammograms, some parts of the breast appear more dense than others, and the greater the breast density, the greater the risk for breast cancer. The research team is trying to improve on current methods of measuring breast density, which aren't accurate enough to be useful.

Breast Stromal Genes Act as Early Markers of Malignancy.

Thea Tlsty, Ph.D., at the University of California, San Francisco, is collaborating with Stephanie Jeffrey at Stanford University to investigate the potential of detecting cancer by examining the stromal cells, which are connective tissue and supporting cells in the breast. Breast cancer usually arises in epithelial cells, which are supported by stromal cells. The research team is looking for abnormalities in the genes of stromal cells that are adjacent to breast cancer cells and precancerous cells.