Earlier Detection: Improving the 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. Earlier detection combined with improvements in treatment has led to a 25 percent 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 breast cancer at its earliest stage and distinguish harmless breast abnormalities from cancer. Mammograms don’t provide diagnostic information, such as tumor aggression.

Research Conclusions

Four CBCRP grants under the Earlier Detection topic were completed in 2003. Three of these grants supported research that would involve the establishment of biomarkers, and one grant involves a novel imaging technology.

3rd Symposium on the Intraductal Approach to Breast Cancer.
Susan Love, M.D., is a pioneer in breast cancer and women’s health issues. In addition, Dr. Love supports a novel research topic that might someday give physicians a new avenue for detection, prognosis, and even treatment of breast cancer. The CBCRP funded the Susan Love MD Breast Cancer Research Foundation, Santa Barbara, to bring together scientists, physicians, and breast cancer advocates from California and throughout the world. They discussed research into detecting breast cancer by examining the fluids and cells in the lining of the milk ducts of the breast, the place where 95 percent of breast cancers begin. The intraductal approach provides direct access to the inside of the lining of the breast. A typical scenario is to collect nipple aspirate fluid (NAF), which contains cells and secreted proteins. Another approach is routine operative breast endoscopy (ROBE), which can directly visualize abnormal regions with tiny video cameras. Solutions can be introduced through the nipple opening and recovered so the protein constituent can be analyzed for biomarkers of cancer. The CBCRP was interested in funding this meeting because of the high potential to develop new collaborations between basic scientists and clinicians.

Two-Dimensional Magnetic Resonance Spectroscopy of Breast Tumors.
Nathaniel Wyckoff, Ph.D., at the University of California, Los Angeles, investigated whether a new technology, a variation of the widely used MRI (Magnetic Resonance Imaging) test, can be used to detect breast cancer. Dr. Wyckoff investigated two-dimensional magnetic resonance spectroscopy, a technique that detects the presence of various chemicals in tissue. The research team used the technique to create a chemical profile of the breasts of 30 healthy women, 13 women with invasive breast cancer, and two women with benign breast tumors. Magnetic resonance imaging worked well to tell the difference between breast cancer tissue and healthy breast gland tissue. It also worked well to tell the difference between breast cancer tissue and benign breast tumor tissue, although the number of women in this study with benign tumors was so small that more research needs to be done to confirm this. The technique worked less well to tell the difference between breast cancer tissue and healthy breast fatty tissue.

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, M.D., at the University of California, Davis, investigated whether measuring the level of a fat found in the blood, lysophosphatidlycholine (LPC), can be used to detect breast cancer. The research team is also investigating whether LPC blood levels can be used to detect a recurrence of the disease, or reveal whether treatment is working against breast cancer that has spread to other body parts. They have recruited 98 women; 57 are recently diagnosed and under treatment, 19 have had breast cancer that has not recurred, 9 women are being treated for breast cancer that has spread to other places in their bodies, and 12 women have not had breast cancer. The research team has collected blood samples from some of the women and will finish this research with funding from another research funding agency.

Discovery and Study of Breast Cancer Secreted Proteins.
Elizabeth Williamson, Ph.D., at Cedars-Sinai Medical Center, Los Angeles, originally tried to identify proteins breast tumors secrete into the bloodstream that could become the basis for a blood test to detect the disease. She was unable to find any. However, she discovered a protein, p27Kip1, which is present in cells with normal BRCA1 genes, but barely present, or even absent, in cells that have the BRCA1 mutation that, which leads to a higher chance of breast cancer. Further research showed that lack of this protein in cells may contribute to those cells developing breast cancer. A therapy based on stimulating cells to produce this protein could prevent the development of breast cancer. Results of her study were published in Oncogene 21 (2002): 21, 3199-3206.

Research in Progress

A number of ongoing CBCRP grants in the topic of Earlier Detection reported substantial progress in 2003.

Breast CT for Much Earlier Detection of Breast Cancer.
Young women and women whose breast tissue looks dense on a mammogram are at higher risk for having tumors missed when they have a mammogram. These women, in particular, need a more accurate and sensitive detection method. 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, more comfortably than a mammogram, because there would be no breast compression. This year, the team will complete the construction of the scanner and then test it on volunteers who have and do not have breast cancer. A recent article was published in the American Institute of Physics
Conference Proceedings 682 (2003):308.

Non-Invasive Optical Characterization of Breast Physiology.
Bruce Tromberg, Ph.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 device 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 hemoglobin, a component of blood. In the past year, the team tested the instrument on 17 women, many of them breast cancer patients, at UC Irvine and UC San Francisco. The scanner has potential for earlier detection of breast cancer and also for monitoring whether therapy is shrinking a tumor. It could also lead to a reduction in biopsies. The CBCRP first funded Dr. Tromberg to test this innovative idea in 1996, and again in 2000. As a result, the National Institutes of Health recently provided UC Irvine with a $7 million grant to continue this technology across a range of medical uses. This is an example of start-up funds from the CBCRP leading to much greater funding from larger funding institutions. The optical detection basic science underlying this technology was recently published in the Journal of Biomedical Optics 7 (2002):60-71.

Clinical Utility of Breast Cancer DNA Markers in Plasma.
David Hoon, Ph.D., of the John Wayne Cancer Institute, Santa Monica, has shown that DNA specific to breast cancer can be detected in the blood and bone marrow of breast cancer patients. The team has found that DNA markers, parts of the DNA that are specific to the tumors, 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 is evaluating how the presence of these markers compares with other ways to test the progress of a breast tumor. They have developed a more efficient method for testing blood for levels of multiple DNA markers, and are developing software to aid in analyzing the results of the test. 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. This research led to a publication in Cancer Research 63 (2003):1884-7.

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, has found that when a woman’s tumor has the protein LEA.135 on the surface of at least some cells, her cancer is less likely to recur and she is more likely to survive. The team developed a method for measuring LEA.135 and used it to test tissue samples from biopsies of 387 patients. However, measuring LEA.135 does not help predict whether chemotherapy or preventive therapy with the drug tamoxifen will be effective against a particular tumor. This research resulted in a publication in Anticancer Research 22 (2002):2933-7.

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 measure 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. However, current methods of measuring breast density aren’t accurate enough to be useful. The research team has adapted two techniques already used to measure bone density, called dual (DXA) and single (SXA) x-ray absorptiometry, and have succeeded in accurately measuring breast density with both. They believe these methods can become part of a routine mammogram exam to better identify a woman’s breast cancer risk. This research resulted in a publication in Radiology 223 (2002):554-7.

Research Initiated in 2003

Combined Optical and Ultrasound Imaging for Breast Cancer.
Sean Merritt, working in the laboratory of Dr. Bruce Tromberg at the Beckman Laser Institute at the University of California, Irvine, is developing and testing a possible new device to detect breast tumors more accurately than mammograms. The portable, hand-held device combines ultrasound with diffuse optical tomography (DOT). DOT uses light to measure the amounts of water, fat, and hemoglobin (a part of blood) in breast tissue. This research grows out of another CBCRP-funded project (see “Non-Invasive Optical Characterization of Breast Physiology,” described above, in this section under “Research in Progress.”)