U.S. Army Medical Research and Materiel Command
Point of Contact:
Chuck Dasey, (301) 619-7071
July 20, 2000
For Immediate Release:
Using the Body's Anticancer Defenses to Guide and Improve Breast Cancer Treatment
Research Results from "Era of Hope" Department of Defense Breast Cancer Research Program Meeting
ATLANTA, June 9, 2000 - Three studies presented at the "Era of Hope" Department of Defense Breast Cancer Research Program meeting describe ways in which the body's own genes and immune system are being used to inform new directions in treatment decisions and develop promising new therapeutic approaches.
New Data Indicate that Overexpressed HER-2/neu May Not Always be Problematic
Research presented here may change the way clinicians interpret HER-2/neu, a growth factor protein thought to have prognostic significance in breast cancer.
According to findings from a recent study, overexpression of HER-2/neu - which has been tied to poor prognosis - is not necessarily a problem. New data suggest that the protein has to be switched on, or "activated," to exert a harmful effect, and in many women whose tumors overexpress the substance, researchers found that it is dormant.
"If this work holds up after larger follow-up studies, it may help guide treatment choices for women with breast cancer," said Michael P. DiGiovanna, M.D., Ph.D., assistant professor of medicine and pharmacology at Yale University School of Medicine in New Haven, CT. "For example, it may help determine which women need adjuvant therapy and the aggressiveness of that treatment."
Normal cells have two copies of the HER-2/neu gene and a low amount of cell-surface HER-2/neu protein. In an estimated 30% of women with breast cancer, the tumor has extra copies of the HER-2/neu gene and produces excess cell-surface HER-2/neu protein. Investigators examined breast cancer specimens for evidence of phosphorylated HER-2/neu (Pneu), the protein's activated form. They detected Pneu in 12% of breast cancers that overexpressed HER-2/neu. Women with overexpressed but inactive HER-2/neu had clinical profiles similar to those of women with normal levels of the protein, indicating less aggressive tumors. However, women with detectable Pneu tended to have clinical features that are strongly linked to poor prognosis, including more cancer-involved lymph nodes, estrogen receptor-negative tumors (meaning that they are not candidates for treatment with hormonal therapies such as tamoxifen), and abnormal p53, a tumor-suppressor gene. When normal p53 senses cell damage, it orders imperfect cells to die. By failing to trigger this "suicide pathway," abnormal p53 may allow cancer cells damaged by chemotherapy to survive and replicate. The women with detectable Pneu also had an increased rate of relapse and a decreased survival.
On the basis of this study, the Yale team has expanded its related research to refine the utility of HER-2/neu status in treatment decisions. Three new breast cancer trials will investigate whether women with overexpressed and activated HER-2/neu have (1) worse response to tamoxifen; (2) better response to Herceptin (trastuzumab), a monoclonal antibody that fits into HER-2/neu, bumping the proteins from their designated docking bays and preventing delivery of their tumor growth instructions; and (3) altered response to a common combination breast cancer treatment regimen known as CAF (cyclophosphamide, Adriamycin, and 5-fluorouracil).
Intra-Tumor Delivery of IL-12 Prolongs Survival and Lessens Toxicity
A single injection of a gene encoding a protein produced by the immune system caused shrinkage of breast cancer metastases in the livers of mice and significantly extended the animals' survival, researchers reported today.
"What distinguishes this approach, called immunomodulatory gene therapy, from other types of gene therapy is that the gene is injected directly into the tumor, where it triggers the production of disease-fighting substances - and kills the tumors, allowing the animals to live longer," said Savio L.C. Woo, Ph.D., professor and director, Institute of Gene Therapy, Mount Sinai School of Medicine, NY.
Twenty to 40% of mice receiving the gene injection survived for more than 160 days, whereas control mice all died within 75 days, reported Dr. Woo and his colleagues. The gene is "packaged" inside a common cold virus that has been genetically altered so that it cannot reproduce but can stimulate production of interleukin-12 (IL-12), a naturally occurring protein that boosts the body's disease-fighting mechanisms. The process creates a tiny "biological factory" that makes a constant supply of IL-12 right inside the tumor, which in turn continually stimulates the recruitment of natural killer cells. Natural killer cells are white blood cells that give off powerful chemicals that bind to and kill foreign invaders in the body.
According to Dr. Woo, another advantage of intratumoral delivery of the IL-12 gene is reduced toxicity compared with intravenous delivery of the IL-12 protein. IL-12 quickly becomes toxic when injected into the blood, but with intratumoral delivery of the gene, the concentration of IL-12 is very high within the tumor and very low in the blood.
Upon clearance from both the U.S. Food and Drug Administration and the National Institutes of Health, Woo and his colleagues hope to begin a Phase I clinical trial later this year to test the safety of this unique approach in patients whose breast cancer has spread to the liver. In patients where the breast cancer has spread to other organs, current treatments result in complete remission only 10% of the time, and average patient survival ranges from seven to 16 months.
Anti-Angiogenesis Therapy and Immunotherapy Better Together than Either Alone
A new approach involving the combination of two experimental cancer treatments - antiangiogenesis compounds and immunotherapy - has demonstrated a more potent antitumor effect than either modality used separately, reported investigators from the University of Pittsburgh, PA.
"Though this is very early research, it is the first time that immune therapy and antiangiogenic agents have been used together, and the first time these antiangiogenic compounds have been studied in breast cancer," said lead investigator Elieser Gorelik, M.D., Ph.D., professor of pathology at the university.
Endostatin and angiostatin are proteins that inhibit angiogenesis - the formation of new blood vessels that tumors need for continued growth. High expectations attended the discovery of these compounds, but their promise is yet to be demonstrated in human studies. Used alone, they destroy new blood vessels but not all tumor cells that lurk around established blood vessels. When treatment stops, even tumors that shrink resume growth.
"We decided to investigate whether we could improve results by double-teaming the tumors - first by cutting off new blood supplies with endostatin or angiostatin, then by prompting the body's immune system to launch an attack on the remaining tumor cells," explained Dr. Gorelik.
After testing several experimental cancer lines, Gorelik and colleagues concluded that the angiogenesis inhibitors had a stronger impact against immunogenic tumors - those that provoke an immune system response - than against non-immunogenic tumors. This effect was influenced strongly by the immune status of the animals. In mice bred to have deficient immune systems, angiostatin and endostatin had significantly less therapeutic effect than in normal (immunocompetent) mice. Researchers also found that when they stimulated the immune system by antitumor vaccination or with IL-12, the antitumor effects of the angiogenesis inhibitors increased. Immunostimulation and endostatin treatment achieved a complete regression of established tumors in approximately 50% of the immunocompetent mice, compared with no regression in mice treated with either endostatin or immunotherapy alone. In this study, immunotherapy was given shortly before antiangiogenesis treatment stopped and again several days later.
Since the researchers found that endostatin showed a stronger anticancer effect than angiostatin, it was the only angiogenesis inhibitor used in this breast cancer study and will remain the focus for future research by this group. The researchers acknowledge the small scale of the study but are optimistic about the potential for benefit in stimulating the immune system to complement angiogenesis inhibition and destroy residual cancer cells. This research initiative was funded with a Department of Defense Breast Cancer Research Program "IDEA" grant, an award category designed to support novel, untested and high-risk ideas, as well as the participation of young, promising scientists. "Based on our evidence from experiments with mice, it seems promising to consider testing a combination of immunotherapy and endostatin to treat breast and other cancers in clinical trials," said Dr. Gorelik. "A few clinical trials of endostatin have begun and so far, no serious side effects or toxicity have been observed."
For now, the laborious process of creating endostatin limits the quantity necessary to conduct large trials in animal models and eventually for human studies. The compound can be created from bacteria or from yeast. The bacteria-based process yields an insoluble form that can be administered to mice as a slow-release agent but is unsuitable for use in humans. Although the yeast-based process produces a soluble compound appropriate for human clinical trials, the yield is very low - some 10 times less than the yield from bacteria. For their studies, the University of Pittsburgh group succeeded in creating soluble murine endostatin from Escherichia coli bacteria (an article describing this process is being drafted by the researchers). They will focus future efforts on producing bacteria-derived human endostatin in soluble form, to increase supply and reduce the cost of human endostatin for clinical trials.
"Era of Hope" is a forum for the presentation of research supported by the U.S. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of 53 congressional research programs managed by the U.S. Army Medical Research and Materiel Command, the BCRP has received more than $1 billion to date from Congress for innovative breast cancer research.
"Signaling Status of HER-2/neu as a Prognostic Factor in Breast Cancer"
Michael P. DiGiovanna, Ann D. Thor, Susan Edgerton, Dan Moore II, Katherine M. Kasowitz, Christopher C. Benz, David F. Stern
- General Session: Friday, June 9, 1:45 p.m. - 3:15 p.m., Grand Salon D
- Poster Session: Saturday, June 10, 6:40 p.m. - 8:10 p.m., Galleria, Posterboard N-4
"IL-12 Gene Therapy for Metastatic Breast Carcinoma"
Savio L.C. Woo
- General Session: Friday, June 9, 3:30 p.m. - 5:00 p.m., Grand Salon C
- Poster Session: Sunday, June 11, 6:20 p.m. - 8:00 p.m., Galleria, Posterboard AA-26
"Increased Efficacy of Angiostatin and Endostatin Therapy by Stimulation of Antitumor Immunity"
Elieser Gorelik, Zhen-yu Zhu, Xiaojun Huang, Qun Zhao, Michael Wang, Ronald Herberman, Mengfeng Li
- General Session: Sunday, June 11, 1:30 p.m. - 3:00 p.m., Grand Salon E
- Poster Session: Sunday, June 11, 6:20 p.m. - 8:00 p.m., Galleria, Posterboard Y-15