1. What is the Long Island Breast Cancer Study Project?

The Long Island Breast Cancer Study Project (LIBCSP) is an investigation of possible environmental causes of breast cancer in Suffolk, Nassau, and Schoharie counties in New York and in Tolland County, Conn. It is sponsored by the National Cancer Institute (NCI), in collaboration with the National Institute of Environmental Health Sciences (NIEHS). The project consists of more than 10 studies that include human population (epidemiologic) studies, a family breast and ovarian cancer registry, and laboratory research designed to help explain the development of breast cancer. The project also includes the creation of a new research tool, a Geographic Information System (GIS-H) for Breast Cancer Studies on Long Island, which allows researchers to explore new hypotheses on environmental risk factors for breast cancer.

2. Why was the project done?

A pattern of elevated mortality rates (the number of deaths per year) for female breast cancer extending from the Mid-Atlantic through the Northeastern states has persisted for many years. Established risk factors are believed to be largely responsible, but the remaining reasons are unknown. Further, incidence rates (the number of breast cancer cases newly diagnosed each year) in Nassau and Suffolk counties in New York and in Tolland County, Conn., were above the U.S. average at the time the Long Island project began. For this reason, the LIBCSP and other studies have been undertaken to try to learn if there are environmental exposures that may be responsible.

Public Law 103-43, enacted in 1993, directed that NCI conduct a study of "potential environmental and other risks contributing to the incidence of breast cancer" in Nassau, Suffolk, and Schoharie counties in New York and in Tolland County, Conn. The law also stated that the study on Long Island "should include the use of a geographic system to evaluate the current and past exposure of individuals, including direct monitoring and cumulative estimates of exposure to (1) contaminated drinking water; (2) sources of indoor and ambient air pollution, including emissions from aircraft; (3) electromagnetic fields; (4) pesticides and other toxic chemicals; (5) hazardous and municipal waste; and (6) such other factors as the director [of NCI] determines to be appropriate."

3. What is the major study in the LIBCSP?

The main research study of the LIBCSP is the Breast Cancer and the Environment on Long Island Study, a large, population-based study of women in Nassau and Suffolk counties (Long Island) to determine if certain environmental contaminants increase the risk of breast cancer. The primary goals of this study were to determine if polycyclic aromatic hydrocarbons (PAH), a pollutant caused by incomplete combustion of various chemicals including diesel fuel and cigarette smoke, and organochlorine compounds, chemicals found in many pesticides, are associated with increased risk for breast cancer among women on Long Island. The organochlorine compounds studied were the pesticides DDT and its metabolite DDE, chlordane, dieldrin, and polychlorinated biphenyls (PCBs). PCBs are a family of chemicals used in transformers, capacitators, and other electrical equipment. They are no longer used in new equipment; however, they remain persistent in the environment.

4. What are the results of the Breast Cancer and the Environment on Long Island Study?

The results of this study are reported in three scientific papers published in August 2002 by Marilie D. Gammon, Ph.D., University of North Carolina at Chapel Hill, and her coworkers. The first paper describes the full study population and research methods, and the established risk factors for breast cancer found in the group. It appears in Breast Cancer Research and Treatment.¹ Many of the well-known breast cancer risk factors were confirmed in the study. These risk factors included increasing age, having a family history of breast cancer, having a first child at a later age (age 28 or older in this study), never having given birth to a child, and having higher income.

In addition, some recognized risk factors were not found to be associated with increased risk for breast cancer among all women in the study. These included early age at beginning of menstruation (menarche) and having attained a higher level of education. The researchers are conducting more detailed analyses to further explore these results.

The study's major findings were reported in two papers in Cancer Epidemiology, Biomarkers & Prevention². The researchers found that organochlorine compounds are not associated with the elevated rates of breast cancer on Long Island. However, the researchers say that it is possible that breast cancer risk in some individuals may be associated with organochlorine exposures because of individual differences in metabolism and ability to repair DNA damage. Dr. Gammon and members of her research team are continuing to investigate these possibilities.

The researchers also found that exposure to PAHs was associated with a modest increased risk for breast cancer. In this portion of the study, the scientists measured the level of binding of PAHs to DNA (forming what is called PAH-DNA adducts) in blood samples taken from the study participants. Formation of PAH-DNA adducts is believed to be necessary for cancer development. Women who had the highest levels of PAH-DNA adducts had a modest 50 percent increased risk for breast cancer compared to women with the lowest levels of adducts. The new finding is consistent with the few, much smaller epidemiologic studies and suggests the need for additional research in other populations.

While Dr. Gammon's study did not identify specific environmental factors as a cause for breast cancer on Long Island, the study is important in that it provides new clues for future studies. The study makes a valuable contribution to our foundation for understanding environmental factors and how they related to the risk of breast cancer.

NCI will continue to study the role of the environment in breast cancer to unravel the complexity of exposure diversity in the environment, the importance of the timing of exposure, and the role of genetic susceptibility.

5. Why is 50 percent increased risk considered modest?

Compared to other known risk factors for cancer, a 50 percent increase in risk is modest. For example, smoking increases the risk of developing lung cancer by 900 percent to 1,000 percent. A family history of breast cancer increases risk by 100 percent to 200 percent.

6. Why did the study focus on organochlorine compounds and PAHs?

The study focused on organochlorine compounds because smaller epidemiologic studies had suggested that the pesticide DDT, which is an organochlorine compound that has been banned in the United States since 1972, might be associated with increased risk for breast cancer. In addition, DDT and its metabolites are known to cause liver cancer in rats. This early research prompted a variety of studies in different populations to further examine a link between cancer and organochlorine compounds.

PAHs were another focus of the study because these compounds are known to cause breast cancer in rodents. In addition, a few small epidemiologic studies suggested a possible association between these chemical agents and increased risk for breast cancer.

Another reason for studying organochlorine compounds and PAHs was that scientists can detect evidence in the body of past exposure to these chemicals. Organochlorine pesticides can persist in the body for more than a decade, while PAHs can persist for a few months. In contrast, researchers do not have ways to detect past exposures to most chemicals. This was an important consideration because breast cancer is believed to be caused by risk factors, or the accumulation of risk factors, that occurred many years before the cancer can be detected.

7. Who participated in the study?

The study included 1,508 women living in Nassau and Suffolk counties who were newly diagnosed with in situ or invasive breast cancer over a 1-year period beginning August 1996, and a similar number of women who did not have cancer. In situ breast cancer is early cancer that has not spread to neighboring tissue.

8. How was the study conducted?

The study participants completed a questionnaire administered by interview in their homes, and the majority provided pre- and post-treatment blood samples and urine samples. In addition, a sample of participants who had lived in their homes for at least 15 years participated in a study in which house dust, tap water, and yard soil samples were collected and tested for organochlorine compounds and PAHs.

9. What have other published studies shown about the relationship between PAHs and organochlorines and breast cancer?

Over the past few years, researchers have been reporting their findings about PAHs and organochlorines. Most, but not all, of these studies have reported no evidence of an association between exposure to the chemical compounds and increased risk for breast cancer. This Long Island project is the largest of these studies.

10. Is additional research planned to follow up on the Breast Cancer and the Environment on Long Island Study?

There are many studies under way that are using the population, data, or specimens from the Breast Cancer and the Environment on Long Island Study.

•Dr. Gammon and colleagues are continuing to follow the women who participated in the study to determine whether organochlorine compounds (including DDT/DDE, PCBs), PAH, and lifestyle factors influence survival of Long Island women diagnosed with breast cancer. This study is funded by NCI.

&#149Dr. Gammon is also examining p53 protein in tumor tissue. P53 is a gene which normally regulates the cell cycle and protects the cell from damage to its genome. Mutations, or changes, in this gene cause cells to develop cancerous abnormalities. This p53 study is funded by the U.S. Department of Defense (DOD).

•Habibul Ahsan, M.D., of Columbia University, New York, and colleagues are examining whether certain common variations in the sequence of DNA involved in the biosynthesis and metabolism of estrogen and environmental carcinogens are associated with risk for breast cancer. This study is funded by DOD, NCI, and the Cancer Research Foundation of America.

•Regina Santella, Ph.D., also of Columbia University, and colleagues are re-analyzing the PAH-DNA adducts from the Breast Cancer and the Environment on Long Island Study using a different assay, in order to learn more about the etiology of breast cancer. An assay is a laboratory test to find and measure the amount of a specific substance. This study is funded by DOD and NCI.

&#149Dr. Gammon and Dr. Santella are examining the role of variants in genes involved in oxidative stress related to environmental contaminants. Oxidative stress is a term used to describe a type of damage to the body due to products derived from the metabolism of oxygen. This research is funded by DOD.

•Rebecca Cleveland, of the University of North Carolina at Chapel Hill, and Dr. Gammon are examining variants of insulin-like growth factor (IGF-1) in relation to risk for breast cancer. IGF-1 is known to cause proliferation of human breast cancer cells, and also to prevent the bodys clearing of old and damaged cells. This may cause increased growth of tumor cells, in addition to accumulation of breast cells that have mutated to cancerous forms. The study is funded by DOD.

•Geoffrey Kabat, Ph.D., a New York epidemiologist, and colleagues are expanding on research begun in the Breast Cancer and the Environment on Long Island Study to further study estrogen metabolites in urine as potential markers for breast cancer risk. The researchers are using biospecimens from women who are participating in the Metropolitan New York Registry for Breast Cancer. The study is funded by the registry.

•Jia Chen, Ph.D., of Mt. Sinai School of Medicine, New York, and colleagues are studying whether variations in genes involved in the metabolism of folate are related to risk for breast cancer. Folate deficiency may be associated with increased risk for breast cancer. The study is funded by DOD.

11. What other research is being conducted as part of the Long Island Breast Cancer Study Project?

Other studies in the LIBCSP are:

•Electromagnetic Fields (EMF) and Breast Cancer. This population-based case-control study on Long Island is investigating whether EMFs are associated with increased risk for breast cancer. The findings from this research are expected to be reported by mid-2003. The principal investigator of this study is M. Cristina Leske, M.D., M.P.H., of the State University of New York at Stony Brook.

•Epidemiology of Breast Cancer on Long Island. This hospital-based case-control study investigated breast cancer risk in relation to levels of organochlorine pesticide compounds in Nassau and Suffolk counties (Long Island) and Schoharie County, N.Y. The researchers found that increased risk for breast cancer did not appear to be associated with past exposure to organochlorine compounds. There was no association between breast cancer risk and levels of total pesticides or total PCBs. The principal investigator is Steven D. Stellman, Ph.D., American Health Foundation, Valhalla, N.Y., now at Columbia University, New York³.

•Organochlorines and Risk of Breast Cancer. This pilot hospital-based case-control study investigated the relationship between exposure to organochlorine compounds and risk for breast cancer in Tolland County, Conn. Data on the Tolland County study population were included in a larger hospital-based case-control study of women from Connecticut that did not find an association between organochlorine compounds and increased risk for breast cancer. The principal investigator is Tongzhang Zheng, M.D., Sc.D., Yale University, New Haven, Conn ⁴.

•Reducing Barriers to Use of Breast Cancer Screening. This study investigated whether a telephone counseling intervention aimed at women who are known to underuse breast cancer screening can, with or without an accompanying educational intervention for their physicians, increase use of breast cancer screening. Women who had a previous mammogram at the start of the study and who subsequently received telephone counseling were more likely to become regular mammography users than women who did not receive counseling. In addition, the findings suggested that the educational intervention for physicians is associated with initiation of mammography use among women who have never had a mammography. More research with larger samples is needed to confirm this finding. The principal investigator is Dorothy S. Lane, M.D., Ph.D., State University of New York at Stony Brook⁵.

•Metropolitan New York Registry of Breast Cancer Families. The registry is recruiting families who have a history of breast and/or ovarian cancer. Participants are asked to contribute information, blood, and urine samples that can be used for studies on the causes of these diseases. The registry is one of six international registry sites funded by NCI to provide researchers a source of information and specimens to speed their investigations into the causes of breast cancer. Rubie Senie, Ph.D., Columbia University, is the principal investigator. Families who are interested in participating in the registry are welcome to call 1-888-METRO-08 (1-888-638-7608).

•Environmental Exposures and Breast Cancer on Long Island. This investigation is being conducted to determine whether length of residence in close proximity to hazardous waste sites, industrial sites, or toxic release inventory sites; prior land use (for example, farm land); and exposure to various chemicals in drinking water may increase risk for breast cancer on Long Island. Findings are expected to be reported in 2003. The principal investigator is Erin O'Leary, Ph.D., State University of New York at Stony Brook.

•Estrogen Metabolites as Biomarkers for Breast Cancer Risk. In this study, investigators examined whether differences in the way women's bodies process the natural hormone estrogen may be related to breast cancer risk. Estrogen is metabolized by two main, competing pathways, either to 2-hydroxyestrone or to 16-alpha-hydroxyestrone. Some research has suggested that the balance between the estrogen metabolite 16-alpha-hydroxyestrone, which has been associated with breast cancer, and 2-hydroxyestrone, which has not, may affect risk for the disease. The researchers found that postmenopausal women with very low levels of the "good" metabolite relative to the "bad" metabolite had a greatly increased risk of breast cancer, compared to women with high levels of the "good" metabolite. Because of the small number of study participants, further study is needed to confirm the findings. The principal investigator is H. Leon Bradlow, Ph.D., Strang Cancer Prevention Laboratory, New York⁶.

•Regulation of Scatter Factor Expression in Breast Cancer. This research evaluated how a growth factor called scatter factor may regulate growth of breast cancer. Using tissue samples from Long Island women, the scientists found that levels of scatter factor are higher in invasive breast cancers than in non-invasive cancers. It also causes human breast cancer cells to move faster and to be more invasive in cell cultures. Further, the growth factor induces breast cells to produce an enzyme that degrades tissue, thus facilitating tumor invasion, and stimulates formation of new blood vessels, which is essential for tumor growth and spread. The principal investigator is Eliot M. Rosen, M.D., Ph.D., Long Island Jewish Medical Center, New Hyde Park, N.Y.⁷

•RDA Analysis of Breast Cancer. The study examined genetic changes in breast tumor tissue from patients on Long Island using a technique called representational difference analysis (RDA). Certain alterations in genes may be linked to environmental exposures, and certain mutations may be characteristic of specific exposures. The principal investigator is Michael H. Wigler, Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.⁸

12. What is the Geographic Information System (GIS-H) for Breast Cancer Studieson Long Island?

In the spring of 2001, NCI completed development of a prototype health-related geographic information system (GIS-H) for Long Island as part of the LIBCSP. This advanced research tool provides scientists a new mechanism to investigate relationships between breast cancer and the environment on Long Island. It also enables researchers to estimate exposure to environmental contamination.

GISs are powerful computer systems that permit layers of information to be superimposed and manipulated. The systems consist of hardware, software, and data tables. The "H" in GIS-H stands for "health," because the system potentially can be used for research on other types of cancer, and other diseases and conditions.

The GIS-H consists of more than 80 databases that have geographic, demographic, health, and environmental data on Nassau and Suffolk counties and, to a lesser extent, on surrounding counties. It also has statistical and analytical tools for researchers. Researchers are welcome to apply to use the system, and information about GIS-H is available at http://www.healthgis-li.com.

The GIS-H also will provide an internet mapping facility for the public. Visitors will be able to see and use some of the content and features of the GIS-H without needing special computer skills. They may choose from a list of interactive maps available on the Web site or choose to install the ArcExplorer mapping software on their computers. This software allows visitors to access GIS-H map services to construct their own maps.

The GIS-H was developed and is maintained by Titan Systems, Inc. (formerly AverStar, Inc.), Vienna, Va., under a contract with NCI.

13. What additional resources are available about the possible relationship of theenvironment and risk of breast cancer?

The Long Island Breast Cancer Study Project Web site (http://epi.grants.cancer.gov/LIBCSP)

"Cancer and the Environment." This fact sheet is a compilation of information and resources on cancer and the environment (http://newscenter.cancer.gov/pressreleases/LIBCSPresource.html .

"Cancer Clusters." <http://cis.nci.nih.gov/fact/3_58.htm> This fact sheet describes cancer clusters and provides resources for reporting suspected clusters.

1. Gammon, Marilie, Ph.D., et al. "The Long Island Breast Cancer Study Project: Description of a Multi-institutional Collaboration to Identify Environmental Risk Factors for Breast Cancer," Breast Cancer Research and Treatment, 74:235-254, 2002.

2. Gammon, Marilie, Ph.D., et al. "Environmental Toxins and Breast Cancer on Long Island. I. Polycyclic Aromatic Hydrocarbon (PAH)-DNA Adducts" and "Environmental Toxins and Breast Cancer on Long Island. II. Organochlorine Compound Levels in Blood," Cancer Epidemiology, Biomarkers & Prevention, 11:677-697, 2002.

3. Stellman, Steven, Ph.D. "Breast Cancer Risk in Relation to Adipose Concentrations of Organochlorine Pesticides and Polychlorinated Biphenyls in Long Island, New York," Cancer Epidemiology, Biomarkers & Prevention 9(11):1241-1249, November 2000.

4. Zheng, Tongzhang, M.D., Sc.D. "Environmental Exposure to Hexachlorobenzene (HCB) and Risk of Female Breast Cancer in Connecticut," Cancer Epidemiology Biomarkers & Prevention 8:407?411, May 1999; "Beta-benzene Hexachloride in Breast Adipose Tissue and Risk of Breast Carcinoma," Cancer 85(10):2212-2218, May 15, 1999; "DDE and DDT in Breast Adipose Tissue and Risk of Female Breast Cancer," American Journal of Epidemiology 150:5;453-458, September 1, 1999; "Risk of Female Breast Cancer Associated with Serum Polychlorinated Biphenyls and 1,1-dichloro-2,2'?bis(p-chlorophenyl)ethylene," Cancer Epidemiology, Biomarkers & Prevention 9(2):167-74, February 2000; "Breast Cancer Risk Associated With Congeners of Polychlorinated Biphenyls," American Journal of Epidemiology 152(1): 50-58, July 1, 2000.

5. Lane, Dorothy, M.D., M.P.H. "Methodology for Targeting Physicians for Interventions to Improve Breast Cancer Screening," American Journal of Preventive Medicine 16(4):289-97, May 1999; "Confirmatory Analysis of Opinions Regarding the Pros and Cons of Mammography," Health Psychology 16(5):433-441, September 1997; "Under users of Mammogram Screening: Stage of Adoption in Five U.S. Subpopulations," Preventive Medicine 27(3):478-487, May-June 1998; "Current Perspectives on Physician Barriers to Breast Cancer Screening," Journal of the American Board of Family Practice 12(1):8-15, January-February 1999; "Effectiveness of Telephone Counseling for Mammography: Results from Five Randomized Trials," Preventive Medicine 34(1):90-9, January 2002.

6. Bradlow, H. Leon. "Urinary Estrogen Metabolites and Breast Cancer: A Case-Control Study, "Cancer Epidemiology, Biomarkers & Prevention 6(7):505-509, July 1997.

7. Rosen, Eliot, M.D., Ph.D. "Scatter Factor Protein Levels in Human Breast Cancers," American Journal of Pathology 146(5):1707-1712, November 1996.

8. Wigler, Michael, Ph.D. "Comparative Genomic Analysis of Tumors: Detection of DNA losses and amplification," Proceedings of the National Academy of Sciences 92:151-155, January 1995.

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