The first, a $7 million, four-year Breast Cancer Center of Excellence grant to Fred Hutchinson from the U.S. Department of Defense, will involve investigators from 10 institutions in Seattle, Houston and Los Angeles. (Please see list.)
The second is a grant of nearly $1 million from a unique, multi-year, public-private partnership of the Avon Foundation and the National Cancer Institute called "Progress for Patients." The funds will be split equally among Fred Hutchinson, the University of Alabama, Fox Chase Cancer Center and M.D. Anderson Cancer Center. (Please see sidebar for more details about the Avon/NCI grant.)
Nicole Urban, Sc.D., a member of Fred Hutchinson's Public Health Sciences Division, will serve as principal investigator of both initiatives.
"Our goal for both projects is to evaluate a variety of breast-cancer biomarkers for their contribution to the early detection of breast cancer. Our vision is that a simple blood test could be used along with mammography to detect breast cancer early in the disease process. We are particularly interested in markers that identify aggressive forms of breast cancer that are missed by mammography," said Urban, also a research professor of health services in the UW School of Public Health and Community Medicine.
While mammography indeed saves lives - reducing deaths from breast cancer by up to 30 percent among women over age 50 - it misses about one in five breast cancers overall. Mammography is least effective in detecting cancer in younger women, who tend to have dense breast tissue that is difficult to X-ray. Other limitations of mammography in younger women include a high rate of false positives that result in unnecessary biopsies and the inability to distinguish between aggressive, life-threatening cancers versus slow-growing tumors that may not need treatment.
"Despite decades of research on mammography as a tool for early detection of breast cancer, its efficacy remains in question, and some women still die of the disease despite annual screening," said Nancy Kiviat, M.D., professor of pathology at the UW School of Medicine and head of pathology at Seattle's Harborview Medical Center, who will serve as co-principal investigator of the DoD-funded Breast Cancer Center of Excellence.
"We have an opportunity to dramatically improve breast-cancer detection and diagnosis by complementing mammography with molecular-screening tools that provide information about the genetic and cellular characteristics of their cancer and how it will behave," she said.
The central focus of the DoD project, called the Center for the Evaluation of Biomarkers for Early Detection of Breast Cancer, will be to develop and test a panel of serum biomarkers - substances in the blood, such as proteins, or specific genetic sequences - which are detected in higher-than-normal amounts in women with breast cancer. Blood and tissue samples will be obtained from 1,800 women undergoing mammography, biopsy or breast-cancer surgery during the next four years at two clinical sites: Swedish Medical Center in Seattle and Cedars-Sinai Medical Center in Los Angeles.
Biomarkers to be evaluated will include:
- circulating breast-tumor cells, which can be identified by the fact that they contain specific genetic instructions for making proteins associated with breast tissue, such as the protein mammaglobin;
- growth factors detectable in serum or plasma that are associated with angiogenesis, or blood-vessel development, often present in cancer because tumors need a blood supply to survive. Growth factors to be evaluated include vascular endothelial growth factor, or VEGF, which is associated with 80 percent of breast tumors and is an indicator of poor prognosis among women with estrogen-sensitive tumors;
- lipid markers, or fatty acids, detectable in serum or plasma, which are associated with pathways of cancer development. Preliminary studies with various lipid markers have resulted in breast-cancer detection rates of up to 90 percent with a "false-positive" rate of only 5 percent.
- antibodies to mutated or over-expressed proteins that are associated with aggressive breast cancer, such as Her2/neu and p53, which are found in 30 percent and 50 percent of breast tumors, respectively; and
- other promising new markers that may become available from emerging new technologies such as proteomics, which can identify telltale "protein signatures" in the blood that are linked to diseases such as cancer.
Using biomarkers for cancer screening is not new; single-marker blood tests for prostate and ovarian cancer, for example, have been used widely for more than a decade. An enzyme called PSA, or prostate-specific antigen, is used to detect prostate cancer while it is still localized and treatable, while a protein called CA-125 can flag the recurrence of ovarian cancer. Studies are under way to test the effectiveness of CA-125 in detecting early-stage disease in asymptomatic women. However, no adequate breast-cancer biomarker has yet been identified, perhaps because there is no single pathway to breast-cancer development, Urban said.
"It is unlikely that we will ever find a single marker that will work perfectly to detect and diagnose breast cancer, because breast cancer is not one disease; not all breast cancers look the same at the molecular level," she said. "We challenge the paradigm that a single marker that detects all breast cancer is even necessary. Instead, we will seek a panel of about 10 synergistic markers that can be used in concert with each other."
There are several ways a breast-cancer biomarker panel could be used, Urban said. For example, a woman could have her blood tested in conjunction with her annual screening mammogram. If the mammogram were clearly positive, she would be referred for biopsy. If the mammogram findings were ambiguous, she would be referred for biopsy only if the marker panel suggested a malignancy. If the mammogram were negative but the blood test suggested cancer, she would be referred for additional tests such as MRI, or magnetic-resonance imaging. Such a marker panel also could be used between annual mammograms to find fast-growing cancers at an earlier stage than they would otherwise be identified, especially in high-risk women.
Key to developing such a panel is the ability to determine which markers are mutually complementary and best improve sensitivity when used together. Another key to the success of such a screening tool is the ability to interpret the results in a statistically meaningful way, taking into account the woman's own personal biomarker behavior, including how these levels may naturally fluctuate over time, instead of a "one-size-fits-all" approach to screening. Leading this effort is biostatistician Martin McIntosh, Ph.D., associate member of Fred Hutchinson's Public Health Sciences Division. McIntosh, also a research associate professor of biostatistics at UW, already has developed such statistical methods for ovarian-cancer screening using new biomarker discoveries.
"For early cancer detection, it is much more useful to look at change over time in multiple markers than to take a single snapshot of any single marker," McIntosh said. "For example, in any particular woman, some biomarkers may consistently fluctuate over time, while others may be quite stable. By giving greater weight to the stable markers than the unstable ones, and by monitoring them over time, only small changes, like those expected in early-stage cancer, are needed to signal a positive screen."
Such an approach to early cancer detection is unique, Urban said. "Martin is one of the few statisticians in the world to have studied longitudinal use of marker panels, taking into account a woman's biomarker history when determining whether the results are positive or negative."
Just as synergy among the biomarkers is needed to develop an effective screening tool, so synergy among the DoD project's investigators is key to productive collaboration. This group of investigators, already working together in the area of cancer biomarkers, includes researchers from the following Seattle institutions: Fred Hutchinson, Group Health Cooperative of Puget Sound, Institute for Systems Biology, Pacific Northwest Research Institute, PhenoPath Laboratories, Swedish Medical Center, University of Washington and Virginia Mason Research Center. Other collaborators include M.D. Anderson Cancer Center in Houston and Cedars-Sinai Medical Center in Los Angeles. Collaborators from many of these institutions already have identified potentially useful breast-cancer biomarkers, but their efforts have not yet produced a screening test ready for evaluation in a large-scale study. The Breast Cancer Center of Excellence aims to accelerate such progress by bringing together laboratory investigators, informatics specialists, clinicians and outcomes researchers, among others, to facilitate the translation of laboratory findings to clinical use.
Supporting communication among the 10 participating institutions will be an innovative Web-based knowledge-management system that will allow the investigators to bounce ideas off each other and share real-time information. Rather than being linear and message-based like e-mail, the system is idea-based. Each topic or idea is given its own Web page within the system and researchers then can add their comments and discussion to any of the topics. "It's a way of communicating among any number of people who can post what they have to say on a Web page and allow others to edit. It's like creating a document collaboratively," Urban said. Supporting documents such as summary statistics, timelines, protocols and meeting minutes also can be posted, allowing investigators to jump quickly from discussion to data and references.
The Department of Defense since 1992 has allocated funds for breast-cancer research. Its Congressionally directed medical-research programs also provide funding for prostate cancer, ovarian cancer, chronic myelogenous leukemia, neurofibromatosis and tuberous sclerosis research.
Other institutions that received DoD funding this year to establish a Breast Cancer Center of Excellence were M.D. Anderson Cancer Center, Houston, Texas; Barbara Ann Karmanos Cancer Institute, Detroit, Mich.; Dana-Farber Cancer Institute, Boston, Mass.; and Mayo Clinic Cancer Center, Rochester, Minn.
PARTICIPANTS IN THE BREAST CANCER CENTER OF EXCELLENCE
SEATTLE, WASH.
- Fred Hutchinson - will provide leadership, statistical expertise, clinical coordination and expertise in breast pathology.
- Group Health Cooperative of Puget Sound - will provide risk assessment of women who donate blood and tissue specimens for analysis.
- Institute for Systems Biology - will contribute cutting-edge technology to ensure integration of the newest molecular approaches to genomics and proteomics.
- Pacific Northwest Research Institute - will contribute world-class expertise in immunology and antibody development.
- PhenoPath Laboratories - will provide expertise in markers related to angiogenesis, or blood-vessel growth, and will help evaluate breast biopsies from study participants.
- Swedish Medical Center - will be the primary site for specimen collection, as clinical activities will be carried out mainly at Swedish.
- University of Washington - will contribute laboratory facilities for the processing, analysis and storage of blood and tissue specimens.
- Virginia Mason Research Center - will provide expertise in novel antibody markers.
OTHER SITES
- M.D. Anderson Cancer Center, Houston, Texas - will provide extensive experience in the identification of cancer markers, particularly the use of lysophospholipids as markers in female cancers.
- Cedars-Sinai Medical Center, Los Angeles, Calif. - will provide access to patients undergoing breast biopsy for the collection of blood and tissue samples, as well as expertise in extracting genetic material from tissue. Also will develop and validate a breast-cancer screening panel using multiple markers.
SIDEBAR
The Fred Hutchinson Cancer Research Center will lead a $1 million, four-institution effort to study the validation of a breast-cancer biomarker panel among women at high risk of breast cancer. The study's funding, totaling $998,538, comes from the "Progress for Patients" award program, a unique, multi-year, public-private partnership of the Avon Foundation and the National Cancer Institute.
The program was established in October 2001 with a $20 million pledge of funds raised by the Avon Foundation's Breast Cancer Crusade. The pledge is Avon's largest single award since the Avon Crusade was created a decade ago.
The grant is one of the first six "Progress for Patients" awards totaling $2.5 million that were announced Oct. 1 by the Avon Foundation and NCI. The funds will be used to support innovative, translational science at 10 research institutions.
"Our partnership with the NCI will support the Avon Breast Cancer Crusade's mission to reverse historic disparities in health care while greatly accelerating important research in prevention, detection and treatment of breast cancer," said Kathleen Walas, president of the Avon Foundation.
Nicole Urban, Sc.D., a member of Fred Hutchinson's Public Health Sciences Division, will serve as principal investigator of the biomarker-validation group.
Other participants in the biomarker project are the University of Alabama at Birmingham Comprehensive Cancer Center, Fox Chase Cancer Center in Philadelphia, Pa., and M.D. Anderson Cancer Center in Houston, Texas, all of which house federally funded Specialized Programs in Research Excellence in breast and/or ovarian cancer.
"Such collaboration is crucial in order to pool our access to high-risk women who harbor the BRCA1 or BRCA2 mutation, which increases risk for both breast and ovarian cancer," Urban said.
The Avon Breast Cancer Crusade has generated more than $200 million in the Unites States from 1993 to mid-year 2002 to fund access to care and find a cure for breast cancer. The Avon Breast Cancer Crusade focuses on medically underserved women. Avon is the world's leading corporate supporter of the breast-cancer cause, with programs in nearly 50 countries.
To date, the Avon Breast Cancer Crusade has provided nearly $4.75 million in breast-cancer research funding to Fred Hutchinson. Editor's note: For more information about the "Progress for Patients" Awards Program, contact Michael Miller in the NCI Press Office at 301-496-6641 or Kelly Hammel Lobel in the Avon Press Office at 212-445-8308.
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 41 nationwide. For more information, visit the center's Web site at www.fhcrc.org.
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