Detection, Prognosis, and Treatment

The detection, prognosis, and treatment topics funded by the CBCRP continue to change as novel technologies and approaches come under investigation. CT (computerized tomography) scanning is emerging with new instruments being designed that are dedicated to breast imaging. Also digital tomosynthesis (a new type of mammography), ultrasound and PET technologies are being used to better image the breast and to allow more accurate excision of tumors. For better disease prognosis, several gene expression profiling tests are coming into both commercial use and clinical testing. The expected benefits of genetic testing performed on tumor samples are to allow individualized therapy to spare women the unnecessary side-effects of treatments with no potential benefit—a common outcome with most non-targeted chemotherapeutics. Cancer therapeutic development continues to evolve with a focus on (i) the validation of novel cell targets and an improved understanding of the disease at the genetic and molecular levels, and (ii) an enhanced ability to match patient subgroups with individual drugs or drug combinations to assess efficacy earlier in pre-clinical testing. Alternative therapies and drugs, especially those derived from plants, engender intriguing areas of investigation.

Two research topics are represented in this section:

Research Conclusions

Breast Stromal Genes Act as Early Markers of Malignancy
The earlier that a breast cancer is found, the better the prognosis. Yet with mammography and breast exam, our two current screening techniques, by the time a cancer is found it has probably already been present for about five to eight years. This is why new methods of early detection are needed. Stefanie Jeffrey, M.D., and Thea Tlsty, Ph.D., at the University of California, San Francisco, investigated whether there were changes that occurred in the stroma–the connective tissue and supporting cells in the breast—that could be used to identify an early cancer. (Stromal cells do not actually become cancerous themselves.) Drs. Jeffrey and Tlsty found that there are cancer-associated cells in the stroma of cancer breast tissue that can stimulate the growth of normal breast cells. They are now going to study precancerous tissue, such as hyperplasia and DCIS, to determine when the cells in the stroma begin to act in this fashion. This work could lead to the identification of a molecular “signature” in the stroma and a new method for detecting breast cancer at an earlier stage.

Chemotherapy-Induced Ovarian Damage: Prevention and Impact
For many young women with breast cancer, learning that chemotherapy may result in premature menopause and limit their childbearing potential is devastating. Early menopause is also associated with rapid bone loss, increased risk of cardiovascular disease, low libido, and vaginal atrophy. Hope S. Rugo, M.D., at the University of California, San Francisco, Lynn Westphal, M.D., at Stanford University, Palo Alto, and Lucy Berlin, M.S., of Young Moms with Breast Cancer, Palo Alto, enrolled 12 women between the ages of 35 and 44 with early stage breast cancer in a phase II clinical trial to investigate whether giving the drug triptorelin, which suppresses ovarian functioning, along with chemotherapy could prevent chemotherapy-induced premature menopause from occurring. The team also conducted a qualitative study in which they interviewed 24 women about the impact premature menopause had on their quality of life. This work raised awareness of fertility and menopause concerns within the patient and oncology communities, established relationships between breast oncology and the fertility specialists at UCSF and Stanford, and began to explore one option for reducing chemotherapy-induced premature menopause.

Chinese Herb/Chemotherapy Interactions in Breast Cancer
Traditional Chinese Medicine (TCM), which has been used for centuries to treat cancer, is widely used among breast cancer patients in California today. Yet there have been few controlled clinical trials that have looked at what occurs when the herbs used in TCM are combined with chemotherapy. Michael Campbell, Ph.D., at the University of California, San Francisco, and colleagues used breast cancer cells that had been taken from mice to study how the chemotherapy drug doxorubicin (brand name Adriamycin) interacts with some of the different herbs used in TCM. All of the herbs the team investigated had previously been found in laboratory studies to inhibit cancer cell growth. The team found that most of the Chinese herbs added to the effectiveness of doxorubicin when they were administered simultaneously. However, some of the herbs reduced the effectiveness of chemotherapy when administered simultaneously but increased effectiveness when used before or after drug treatment. Additional research by the team suggested that the Chinese herbs impacted effectiveness by increasing or decreasing how much doxorubicin was taken up by the cancer cells. This work expands our understanding of TCM, could lead to the development of new breast cancer treatments, and may result in new recommendations about which Chinese herbs should not be used by women while undergoing chemotherapy.

Compositional Breast Density as a Risk Factor
Breast density as viewed on mammography is one of the strongest indicators of breast cancer risk. However, the current methods used to measure mammographic breast density are neither precise nor accurate enough to classify risk status or to follow changes in density over time. Steven Cummings , M.D., Karla Kerlikowske, M.D., and John Shepherd, Ph.D., at the University of California, San Francisco, investigated whether x-ray techniques developed to measure bone density, called dual and single x-ray absorptiometry (DXA & SXA), could precisely quantify breast density. In a study of 36 women (18 with breast cancer, 18 without) they found that all three measures—DXA, SXA, and mammographic density—found higher breast density in the women with cancer. The team also found that SXA breast density measurements were associated with other characteristics known to be related to mammographic breast density and breast cancer risk, such as current use of postmenopausal hormone therapy, menopause, and body mass index. In addition, DXA and SXA appeared to have good potential for monitoring changes in breast density. This work could lead to the development of new methods of assessing breast density during routine risk assessment. Findings from this study were published in Radiology 2002; 223(2):554-7.

Cryptic Peptides-Based Vaccines for Breast Tumor Treatment
Her-2/Neu Crossreactive Analogs as Targets for Breast Cancer
About twenty five percent of all women with breast cancer have tumors that are Her-2/neu positive. These tumors have extra copies of the Her-2/neu gene, which results in too many Her-2/neu receptors on the cell’s surface and an overabundance of Her-2/neu protein. This extra protein causes the cell to replicate more than it should. Because Her-2/neu is normally found in the body, it is referred to as a self-protein. The immune system normally does not attack the body’s own proteins, which has made it difficult to develop a vaccine that targets Her-2/neu. Joseph Lustgarten, Ph.D., and colleagues at the Sidney Kimmel Cancer Center, San Diego, identified and then studied a series of small molecules, called cryptic peptides, that mimic or resemble Her-2/neu to see if they could be used as the basis for a cancer vaccine that targets Her-2/neu-positive tumors. After finding that these peptides were not as effective as expected, the team turned its attention to a different small molecule, called a cross-reactive peptide, which appears more promising. They are able to trigger an immune response because they are not normally found in the body. The team received another CBCRP grant that will allow them to continue to study these cross-reactive peptides. This grant allowed them to investigate whether and in what way these cross-reactive peptides can induce an immune response. The goal was to develop a vaccine that could be used to control and eliminate all types of Her-2/neu-positive tumors. They were able to develop a protocol that made the vaccines effective in protecting transgenic mice with a variety of different HER-2/neu mutations from developing tumors. This work could lead to the development of a vaccine that could be used to treat women with tumors that are Her-2/neu positive.

FKBP Proteins as Molecular Targets in Breast Cancer Therapy
The spread of breast cancer cells from the primary tumor to other parts of the body, which is called metastasis, is the major cause of death in cancer patients. To date, there are no drug treatments that are able to successfully target and stop metastases. Sylvia Fong, Ph.D., at the California Pacific Medical Center Research Institute, San Francisco, and colleagues had previously identified a family of proteins, called FKBPs, that can help keep breast cancer from metastasizing in mice, presumably by reducing the invasive ability of the tumor cells. This current project allowed them to conduct the research necessary to demonstrate that FKBP proteins really are functionally involved in breast cancer progression. The team intends to continue to characterize a novel gene that they found to be part of the network regulated by FKBPs and to explore the possibility of using it as a target for a new breast cancer treatment that can inhibit metastases.

Inhibitors of Myc: Novel Drugs for Breast Cancer
If you look inside breast cancer cells, you will see changes in the levels and activities of many proteins that regulate cell growth. One of these proteins, called Myc, can encourage cells to grow faster and make them resistant to anti-cancer drugs. Breast cancers in which Myc is working overtime have been found to be more aggressive—they invade neighboring tissues and grow very rapidly. For Myc to become active, it must first bind to another protein called Max. Peter Vogt, Ph.D, at the Scripps Research Institute, La Jolla, and colleagues screened newly synthesized chemical library that contain tens of thousands of individual drug-like compounds to look for small molecules that could keep Myc from binding to Max. They were able to identify two new types of Myc inhibitors. One class works by getting between Myc and Max, and then prying them apart. The other works by stabilizing Max, which keeps it from responding to Myc. They are now testing these small molecules to see if they inhibit the growth of breast cancer cells in the lab. They are also exploring whether these Myc inhibitors affect the growth of normal cells. This work could lead to the development of new breast cancer treatments. Findings from this research were published in Bioorganic Medical Chemistry 2006;14(8):2660-73.

Novel I3C Regulated Cell Factor in Breast Cancer Cells
Relatively little research has been directed at identifying active ingredients in vegetables that might be effective in breast cancer prevention and treatment. Indole-3-carbinol (I3C), a substance found in cruciferous vegetables, such as cabbage, broccoli, and Brussels sprouts, has been found to inhibit cancer cell growth in tumors that are not hormone sensitive. Gary L. Firestone, Ph.D., at the University of California, Berkeley, and colleagues studied a novel I3C regulated protein to determine what role it plays in I3C’s ability to inhibit tumor growth. They discovered that I3C regulates a larger size form of a protein, called cyclin E, which controls the cell cycle. They also found that breast cancer cells not treated with I3C produce smaller forms of cyclin E, while the larger form is detected after I3C treatment. The identification of this relationship between cyclin E and I3C could lead to the development of new breast cancer treatments for tumors that are not hormone sensitive.

Grants in Progress: 2006

Apogossypol Derivatives for Breast Cancer Therapy
Maurizio Pellechia
The Burnham Institute of Medical Research

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

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

cAMP Antagonists of Protein Kinase as Breast Cancer Drugs
Sanjay Saldahna
Scripps Research Institute

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

Differential Optical Mammography
Gregory Faris and Christopher Comstock
SRI International and University of California, San Diego

Early Breast Cancer Detection Using 3D Ultrasound Tomography
Edward Nelson
University of California, Irvine

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

ID4: A Prognostic Factor of Breast Cancer Metastasis
Dave Hoon
John Wayne Cancer Institute

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann
Scripps Research Institute

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

Molecular Imaging of Breast Cancer Using Breast PET/CT
Ramsey Badawi
University of California, Davis

Removing Respiratory Artifacts in Nuclide Breast Imaging
Brian Thorndyke
Stanford University

Research Initiated in 2006

Factors Influencing Breast Cancer Screening Among Older Thai
Bulaporn Natipagon-Shah and Mary Jo Clark
Thai Health and Information Service and University of California, San Diego

Multilingual Access to Breast Cancer Early Detection
Susan Stewart and Emily Engelstad
University of California, San Francisco and Alameda County Medical Center

In Vivo MRS for Cancer Diagnosis and Treatment Monitoring
Hyeon-Man Baek
University of California, Irvine

Combined Imaging Modalities for Breast Cancer
Gultekin Gulsen
University of California, Irvine

New Technology to Enhance PET Imaging of Breast Cancer
Craig Levin
Stanford University

Chemical Inhibitors of Hsp70 for Breast Cancer
Chung-Wai Shiau
The Burnham Institute of Medical Research

Real-Time 3D Ultrasound Image-Guidance for Breast Surgery
Michael Bax
Stanford University

Sulforaphane: Its Potential for Treatment of Breast Cancer
Olga Azarenko
University of California, Santa Barbara

A Targeted Therapy for Wound-like Breast Cancers
Howard Chang
Stanford University

Artemisinin Disrupts Estrogen Receptor-Alpha and Cell Growth
Gary Firestone
University of California, Berkeley

Breast Tumor Inhibition by Vitamin D in a Mouse Model
David Feldman
Stanford University

Inhibition of Breast Cancer Aggressiveness by Cannabidiol
Sean McAllister
California Pacific Medical Center Research Institute

Intraoperative Assessment of Surgical Lumpectomy Margins
Armando Giuliano
John Wayne Cancer Institute

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Brunhilde Felding-Habermann
Scripps Research Institute

Nur77-derived Peptides as a Novel Breast Cancer Therapy
Xiao-kun Zhang
The Burnham Institute of Medical Research

rADDs: Novel Disintegrins Targeting Breast Cancer
Stephen Swenson
University of Southern California

Topoisomerase-IIa as a Predictor of Anthracycline Response
Michael Press
University of Southern California

Vascular Targeting Therapy for Breast Cancer
Albert Deisseroth
Sidney Kimmel Cancer Center

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann
Scripps Research Institute