Detection, Prognosis, and Treatment

Although early detection of breast cancer does not guarantee a cure, it provides both the patient and the clinician with a wider array of treatment options. Improved imaging technologies may someday replace mammography, which misses many cancers and requires women to undergo unnecessary biopsies and emotional strain. Replacing toxic chemotherapy with targeted therapies that match the specific tumor subtype is emerging as the first step towards individualized therapy. The CBCRP also supports investigations into novel, alternative therapies.

Research Conclusions

Breast CT for Much Earlier Detection of Breast Cancer.
John Boone, Ph.D., and Karen Lindfors, M.D., at University of California, Davis, built the first dedicated breast computerized tomography (CT) scanner. CT scanners are a special kind of X-ray machine producing thin image “slices” that can be reconstructed into three-dimensional pictures. In contrast, a mammogram is a two-dimensional X-ray taken through the entire breast at once, so the resulting image may not detect a tumor obscured by other tissues within the breast. Prior to this research, CT scanning was not considered feasible for breast cancer screening due to unacceptably high radiation doses. The research team was able to show that the radiation dose for breast imaging could be lower and make annual scanning by CT a reality. They also developed a special table for breast imaging that keeps other parts of the body from being exposed to radiation and eliminates breast compression, a major discomfort with mammograms. These solutions make the breast CT scanner a practical alternative to mammograms. The researchers predict this technology will allow radiologists to detect breast cancers the size of a small pea. Mammograms currently detect cancers the size of a garbanzo bean. The new CT breast scanner is now being tested on women with funding from the National Institutes of Health. It will be five years before it is commercially available. Results of the research were published in Medical Physics 31(2):226-35 (2004) and 29(5):869-75 (2002); and Molecular Imaging 3:149-58 (2004).

MRI for High Risk Breast Cancer Screening and Surveillance.
Nola Hylton, Ph.D., John Zeigler, M.D., M.Sc., and Shelley Hwang, M.D., at University of California, San Francisco, worked to evaluate the benefit of magnetic resonance imaging (MRI) screening for women at higher than average risk for breast cancer. MRI can easily detect small cancers and it is more effective than mammograms in the dense breasts of younger women. However, MRI frequently flags tissue as cancerous that turns out to be normal. The technology has also lacked standards and guidelines for equipment, imaging techniques and interpretation. The research team developed several imaging methods to use MRI to characterize breast tissue, along with a breast tissue index that can be used to predict risk for developing breast cancer. The CBCRP has funded Dr. Hylton and another CBCRP-funded researcher, Bruce Tromberg, Ph.D., at University of California, Irvine, to continue research into the combination of MRI and light-based detection. Results from this research were published in Breast Cancer Research and Treatment 88(1)S163 (2004).

Combined Optical and MRI Imaging for Breast Cancer.
Sean Merritt, at University of California, Irvine, changed the aims of this study, with CBCRP approval, to include magnetic resonance imaging (MRI), rather than ultrasound. Using MRI as the standard, he provided validation measurements for a hand-held laser breast scanner that uses infrared light to detect tumors. The scanner was developed at UC Irvine, with CBCRP funding, by Bruce Tromberg, Ph.D., and colleagues. Mr. Merritt developed mathematical formulas for use with the laser scanner’s measurements of bound water in the breast. Differences in water content can be used to distinguish normal breast tissue from cancer. He measured lower bound water in tumor tissue than was expected from MRI measurements. He also validated the scanner’s measurements of deep breast tissue temperature, which can be useful in some breast cancer treatments. Results from this study were published in Technology in Cancer Research and Treatment 2(6):563-9 (2003).

Clinical Utility of Breast Cancer DNA Markers in Serum.
David Hoon, M.Sc, Ph.D., at John Wayne Cancer Institute, Santa Monica, made significant progress toward a blood test to detect breast cancer and to predict how a tumor will progress in the near future. Normal DNA and DNA from tumors both circulate in the blood. The research team developed the first blood test to detect multiple DNA markers, which are patterns in the structure of DNA. The team found that as tumors grow and acquire the ability to spread to other parts of the body, their DNA contains more and more markers that indicate cancer. The presence of some of these markers can be used to get information about a tumor similar to that obtained from examining tumor tissue taken in a biopsy. The team is testing this blood test further, at multiple sites, to see if it can predict or reveal a recurrence of breast cancer in women who have already had the disease, and to validate the usefulness of the test to diagnose and predict the outcome of breast tumors. This research resulted in publications: Annals of the New York Academy of Sciences 945:22-30 (2001), Cancer Research 63(8):1884-7 (2003), and Proceedings of the American Association for Cancer Research 44:563 (2003).

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. Syed Ashrat Imam, M.S., Ph.D., at Huntington Medical Research Institute, Pasadena, investigated LEA-135, a protein found on the surface of some breast cancer cells. The research team examined frozen tissue samples from 367 women who had breast cancer that had spread to nearby lymph nodes. The team found that tumors with a high or moderate number of tumor cells containing LEA-135 had a 46% lower probability of the tumor recurring within ten years. The presence of LEA-135 on tumor cells was not related to whether the tumor depended on the hormones estrogen or progesterone to survive, or to the patient’s age, tumor size, or how far the tumor had progressed at diagnosis. Women whose tumors contained high or moderate levels of LEA-135 had less chance of recurrence regardless of whether they had a lumpectomy or mastectomy, and regardless of whether they had chemotherapy or radiation treatment. This research could lead to a test that could identify women at high risk for a recurrence of breast cancer who could benefit from more aggressive treatment. Results from this research were published in Anticancer Research 22(5):2933-7 (2002).

Patient-Individualized Chemotherapy in Breast Cancer.
The effectiveness of chemotherapy for breast cancer varies highly from patient to patient. As a result, a substantial proportion of patients either receive toxic drugs that do not help target the tumor, or they are not treated with the most effective chemotherapy for their type of breast cancer. Daniel Silverman, M.D., Ph.D., at University of California, Los Angeles, is developing a method to use positron emission tomography (PET) imaging while chemotherapy is being administered to see if the drug is entering a tumor and acting against it. For PET imaging to detect the drug, the drug must be combined chemically (labeled) with radioactive fluorine. The research team succeeded in labeling two commonly used chemotherapy drugs, paclitaxel and cyclophosphamide. The team found both labeled drugs distribute themselves in the blood and organs of mice in the same ways as the drugs without radioactive fluorine. The team uses a micro PET scanner on mice with human breast tumors grafted in them. The micro PET scanner provided information on chemotherapy concentration in tumor and normal tissues. The measurements could be used to forecast whether paclitaxel would be effective against the tumors. Future directions for this research include expanding the number of chemotherapy drugs that can be measured with PET scanning and testing the technology on women with breast cancer. After CBCRP funding ended, Dr. Silverman published this promising PET-based approach for individualized therapy in Molecular Imaging and Biology 14:1-7 (2005).

Herba Scutellaria Barbatae for Metastatic Breast Cancer.
Metastatic breast cancer, cancer that has spread to other parts of the body, is incurable. Most medications used to treat it have toxic side effects and eventually stop working. New, less toxic treatments are needed. Hope Rugo, M.D., at the University of California, San Francisco, investigated an herb traditionally used in Chinese medicine to treat cancer, Scutellaria Barbatae, or skullcap. (It was also at one time considered to be a remedy for rabies, thus its name, “mad dog weed.”) Her research team had previously showed that a liquid form of this herb could kill cancer cells in cultures and in animals. This study was a Phase 1 clinical trial, testing the therapy in 21 women who had already had an average of three treatments for metastatic breast cancer. The initial dose was 350 ml per day of extract in tea form. During the study, the women did not receive any other chemotherapy, hormone therapy, or herbal medicine. Sixteen women could be evaluated for their response to the treatment. The main side effects were mild nausea, diarrhea, headache, vomiting, constipation, and fatigue. The women also complained of the bitter taste of the tea. Four of the sixteen women had stable disease for longer than three months, three for longer than six months, and the treatment shrank five of the women’s tumors. This herbal treatment is safe and tolerable. The tea has been reformulated to taste better and a larger trial is planned. This study has important implications for research into herbal extracts that may have significant anti-tumor effects.

Lactulosamines: Novel, Non-toxic Therapies for Breast Cancer.
Galectins are proteins found in breast tumors cells that promote tumor growth. One of them, galectin-4, helps turn normal breast cells into cancer cells by allowing aging cells to live longer than normal and to continue to form new cells. Margaret Huflejt, Ph.D., at the Sidney Kimmel Cancer Center in San Diego, created a laboratory culture of normal breast cells with extra galectin-4 that allowed these cells to survive in cancer-like conditions. After testing various compounds on these cells, the research team found that a galectin-4 inhibitor killed off the cells and kept them from dividing to form new cells. This makes the galectin-4 inhibitor, which is not toxic, a potential anti-cancer drug. Dr. Huflejt also found antibodies that target parts of galectin molecules in the blood of breast cancer patients. These antibodies also have potential as breast cancer treatments. This research resulted in publications: Glycoconjugate Journal 20(4):247-55 (2004), Proceedings of the National Academy of Sciences, USA 101(49):17033-8 (2004).

Novel Retinoids with Enhanced Anti-Breast Tumor Efficacy.
Marcia Dawson, Ph.D., of The Burnham Institute in La Jolla, had previously identified a compound called APHN that caused the death of breast cancer cells. APHN is a retinoid, a molecule derived from vitamin A. However, the research team discovered that APHN’s ability to kill breast cancer cells was not related to the part of the molecule that resembles vitamin A, and, moreover, that this part of the molecule made APHN too toxic to be used as a treatment. The research team therefore modified APHN’s molecular structure to create a new compound, 3-Cl-AHPC. 3-Cl-AHPC stops breast cancer cells from dividing and triggers the normal process of cell death. It works by stopping the growth and division of specialized cells that form tumor blood vessels. In mice, 3-Cl-AHPC reduces the volume of mammary tumors—the mouse equivalent of breast cancer—by 70–80%, compared to untreated mice. This research resulted in publications: Journal of Medicinal Chemistry 47(14):3518-36 (2004); Blood 102(10):3743-53 (2003).

Enhanced HER-2 Directed Liposomal Therapeutics.
Delivering chemotherapy drugs selectively to breast cancer cells, and leaving normal cells alone, would greatly reduce chemotherapy side effects. Daryl Drummond, Ph.D., of Hermes BioSciences, Inc. in South San Francisco, focused on putting chemotherapy drugs inside microscopic fat particles called liposomes. The liposomes have an antibody fragment attached to them that binds to a protein, the HER2/neu receptor, found on the surface of cells of one type of breast cancer. In addition, Dr. Drummond’s research team developed highly stable liposomes that significantly delay the release of the chemotherapy drug until the liposomes have accumulated in the tumor. This makes it possible to deliver vinca alkaloids, a type of chemotherapy drug that liposomes haven’t effectively delivered in the past and that are too toxic to be delivered systemically. The research team also modified liposomes in a way that improves the action of another chemotherapy drug, doxarabicin. This research provides hope for new, less toxic treatment methods. It was published in Clinical Cancer Research 11(9):3392-401 (2005).

Drug Dose Tailoring Based on Patient-Specific Factors.
Women who have advanced breast cancer receive chemotherapy that can be just as toxic to their bodies as it is to their tumor cells. Chemotherapy doses are now set according to a woman’s height and weight. Individual doses based on the way a woman’s body processes and eliminates the drug would maximize effectiveness and minimize toxicity. Christine Case Lo, of the University of California, San Francisco, found that immune system molecules called cytokines are associated with drug metabolism and elimination from the body. This makes cytokines, which are also involved in inflammation, promising candidates for further research into tailing chemotherapy dosage.

Chinese Herbal Therapy for Symptom Management.
Chinese herbal medicine has been used to treat a variety of diseases for more than a thousand years. It has been suggested that some Chinese herbal combinations may improve immune function. Women with breast cancer sometimes use Chinese herbs to counteract the nausea caused by chemotherapy, but no research had been done, prior to this study by Hope S. Rugo, M.D., at the University of California, San Francisco, as to whether the herbal treatment was safe or effective. The research team conducted a study on women who were treated with nausea-causing chemotherapy for early stage breast cancer. Half of the women received a commonly used Chinese herbal formula called CT101; half received a placebo. Twenty-six women completed the study. The Chinese herbal treatment caused no toxicities and appeared to be safe. However, there were no differences in nausea reduction or immune function between the women who took the Chinese herbs and those who took the placebo. The women in this study were also taking many other necessary medications, which may have affected the results that point to the Chinese herbal treatment being ineffective.

Potential New Drug Therapy for Breast Cancer.
The insulin-like growth factor receptor (IGF-IR) is a protein located on the surface of almost all cells. Activation of this protein contributes to the development of breast cancer cells, stimulates their growth and promotes their survival. The action of this protein limits the effectiveness of several breast cancer treatments. Jack F. Youngren, Ph.D., at the University of California, San Francisco, developed small molecules that inhibit the activity of IGF-IR. The research team synthesized and screened over 200 compounds. Two compounds with slightly different chemical structures, PQ401 and NDGA, showed the most promise. Both of these are a type of compound called diaryl urea. PQ401 was 5 times stronger than NDGA at inhibiting the growth breast cells in lab cultures. This appears to be because PQ401 blocks the series of chemical reactions through which IGF-IR promotes cell survival, and triggers the normal process of cell death that cancer cells have to evade to survive. Both PQ401 and NDGA significantly reduced the growth of breast tumors in mice. These results were published in Breast Cancer Research and Treatment 94(1):37-46 (2005).

Inhibition of Breast Cancer Cell Invasion by Natural Indoles.
The spread of breast cancer to other parts of the body accounts for the majority of deaths from the disease. The chemical indole-3-carbinol (I3C), found in vegetables like broccoli and Brussels sprouts, reduces the spread of breast cancer by decreasing the cells’ ability to move. Christine Brew, Ph.D., at University of California, Berkeley, investigated how I3C works on a molecular level using breast cancer cells growing in a lab culture. She found that I3C dramatically alters two components of cell structure, actin and vinculin. Breast cancer cells have tiny actin filaments that propel them forward. Breast cancer cells treated with I3C don’t have them. Breast cancer cells also have temporary fibers containing vinculin that anchor only the forward part of the cell. Treating these cells with I3C causes them to form fibers that anchor the entire outer surface of the cell. I3C causes these changes by activating a series of chemical reactions in the cells called the RhoA/Rho pathway. Moving is crucial to breast cancer cells being to spread. Using I3C to stop cells from moving should limit their ability to invade other body parts. Additional work supported by the CBCRP involved the ability of I3C to block key elements of the cell cycle in breast cancer cell lines. This research was published in the International Journal of Cancer, 118(4):857-68 (2006)

Retinoids in Combination Therapies Against Breast Cancer.
Retinoids are compounds derived from Vitamin A, with a slightly different chemical structure. Some retinoids kill off cancer cells and, in experiments with animals, have stopped the growth of breast tumors. Angiostatic therapy prevents the formation of blood vessels tumors need to survive, but the treatment doesn’t eliminate the tumor. F. Javier Piedrafita, Ph.D., at the Sidney Kimmel Cancer Center, San Diego, investigated combining these therapies, to enhance their anti-tumor activity and minimize the risk of undesirable side effects, but the attempt did not work.

Grants in Progress: 2005

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Chinese Herb/Chemotherapy Interactions in Breast Cancer
Michael Campbell
University of California, San Francisco

Novel I3C Regulated Cell Cycle Factor in Breast Cancer Cells
Gary L. Firestone
University of California, Berkeley

FKBP Proteins as Molecular Targets in Breast Cancer Therapy
Sylvia Fong
California Pacific Medical Center Research Institute

Dietary Indole Analogs Inhibit Breast Cancer Cell Invasion
Ling Jong
SRI International

UCLA Biomedical Physics Graduate Training in Breast Cancer
Carolyn Kimme-Smith
University of California, Los Angeles

Cryptic Peptide-Based Vaccines for Breast Tumor Treatment
Joseph Lustgarten
The Sidney Kimmel Cancer

Her-2/neu-Crosreactive Analogs as Targets for Breast Cancer
Joseph Lustgarten
Sidney Kimmel Cancer Center

Pilot Studies of Breast Cancer Immunophototherapy
Edward Nelson
University of California, Irvine

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Novel Agents for Breast Cancer Therapy
Maurizo Pellecchia
The Burnham Institute

Chemotherapy-Induced Ovarian Damage: Prevention and Impact
Hope Rugo, Lynn Westfal, and Lucy Berlin
University of California, San Francisco; Stanford University; and Young Moms with Breast Cancer

Compositional Breast Density as a Risk Factor
John A. Shepherd and Steven R. Cummings
Veterans Affairs Medical Center

Breast Stromal Genes Act as Early Markers of Malignancy
Thea Tisty
University of California, San Francisco

Cancer Functional Imaging with Optics and MRI
Bruce Tromberg, Nola Hylton and John Butler
University of California, Irvine

Inhibitors of Myc: Novel Drugs for Breast Cancer
Peter Vogt
Scripps Research Institute

Research Initiated in 2005

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Molecular Imaging of Breast Cancer Using Breast PET/CT
John M. Boone, Ph.D.
University of California, Davis

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann, Ph.D.
The Scripps Research Institute

ID4: A Prognostic Factor of Breast Cancer Metastasis
David S. Hoon, Ph.D.
John Wayne Cancer Institute

HER3 Infidelity and Resistance to Tyrosine Kinase Inhibitors
Mark M. Moasser, M.D.
University of California, San Francisco

Early Breast Cancer Detection Using 3-D Ultrasound Tomography
Thomas R. Nelson, Ph.D.
University of California, San Diego

cAMP Antagonists of Protein Kinase as Breast Cancer Drugs
Sanjay Adrian Saldanha, Ph.D.
The Scripps Research Institute

Removing Respiratory Artifacts in Nuclide Breast Imaging
Brian Thorndyke, Ph.D.
Stanford University

An Approach to Antiestrogen Resistance in Breast Cancer
Oksana V. Tyurina, Ph.D.
University of California, San Diego

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Inhibition of the BRCA2-RAD51 Interaction in Breast Cancer
Jiewen Zhu, Ph.D.
University of California, Irvine