DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Cancer Institute
National Institute of Environmental Health Sciences

INTERIM REPORT ON THE
LONG ISLAND BREAST CANCER STUDY PROJECT

June 2000


Table of Contents

Executive Summary

Geographic variation in breast cancer rates has been well documented, and while some variation may be explained by differences in population distribution of known breast cancer risk factors, researchers and the public are turning to environmental exposures to look for explanations for these variations. The Long Island Breast Cancer Study Project (LIBCSP) is a multistudy research initiative examining the possible role of environmental factors in breast cancer in Suffolk, Nassau, and Schoharie counties in New York and Tolland County, CT where rates of breast cancer incidence are elevated. The project was begun in 1993 in response to Public Law 103-43 (see Appendix A) by the National Cancer Institute (NCI) in collaboration with the National Institute of Environmental Health Sciences (NIEHS) with total funding estimated at $27,294,997 within fiscal years 1993 through 2000 (see Appendix C).

The LIBCSP, the goal of which was to use multiple scientific approaches to study breast cancer on Long Island, consists of human population (epidemiologic) studies, the establishment a family registry for breast and ovarian cancer, and laboratory research on mechanisms of action and susceptibility in breast cancer development. The studies were conducted by scientists at major medical research institutions in the Northeast, and investigators expect to publish their findings in peer-reviewed scientific journals in 2000 and 2001. In addition, in May 1999, NCI awarded a five-year contract to develop and implement the prototype of the geographic information system for health (GIS-H) for Long Island, which will be the first system of its type developed for the study of breast cancer. The GIS-H will provide a new tool for researchers to investigate relationships between breast cancer and the environment, and to estimate exposures to environmental contamination.

The LIBCSP is a complex research effort that has charted new ground in environmental epidemiology. The assessment of environmental exposures and determining their relationship with cancer is difficult. From the project's inception it was clear that new technologies were needed for the measurement and analysis of certain exposures. New biological markers of cumulative exposures were, and continue to be, needed. The LIBCSP investigators made progress in these areas and explored new ways to study the relationships between the environment and breast cancer. However, much remains to be learned about the role of environmental exposures and other risk factors and their interaction with genes in promoting the development of breast cancer; and NCI and NIEHS have a continuing commitment to better understand the way each contributes to an individual's risk of developing cancer.

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Introduction

The Long Island Breast Cancer Study Project (LIBCSP) is part of the overall research approach of the National Institutes of Health (NIH) to investigate the causes of breast cancer and find ways to prevent the disease. The multistudy LIBCSP has been investigating whether environmental factors are responsible for breast cancer in Suffolk, Nassau, and Schoharie counties, NY, and Tolland County, CT. The research began in 1993 in response to Public Law 103-43, June 10, 1993, and has been funded and coordinated by the National Cancer Institute (NCI), in collaboration with the National Institute of Environmental Health Sciences (NIEHS). (See Appendix A)

The law directed that a study be conducted of "potential environmental and other risks contributing in the incidence of breast cancer" in Nassau and Suffolk counties and the two counties with the highest age-adjusted mortality rates for breast cancer during 1983-1987, which were Schoharie County, NY, and Tolland County, CT. In addition, the law directed that the study "shall 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 [NCI] director determines to be appropriate."

The LIBCSP consists of human population (epidemiologic) studies, the establishment of a family breast and ovarian cancer registry, and laboratory research on mechanisms of action and susceptibility in development of breast cancer. Most of these studies have been conducted by scientists at major medical research institutions in the Northeast. The funding periods for most of the grants have ended or will end in the year 2000, and the investigators have either completed their research, or are analyzing their data with the expectation of reporting findings in peer-reviewed scientific journals within the next year or two. Findings from the major studies will be reported in the years 2000 and 2001. (See Appendix B)

An estimated $27,295,000 is being spent for the LIBCSP between fiscal years 1993 through 2000. (See Appendix C) In May 1999, NCI awarded a $4.87 million 5-year contract to develop and implement the prototype geographic information system for health (GIS-H) for breast cancer studies on Long Island. The GIS-H will provide a new tool for researchers to investigate relationships between breast cancer and the environment, and to estimate exposures to environmental contamination. It is expected to be available for pilot studies in mid-2001. The GIS-H for Long Island will be the first system of its type developed for the study of breast cancer.

This report is organized into seven sections. The Introduction states the Congressional mandate for conducting the LIBCSP and summarizes the response from NCI and NIEHS. The Breast Cancer Statistics section provides incidence and mortality rates for the disease for counties included in the Project. The Background section discusses steps taken to carry out the Project and the exposures under study. The Research section describes the extramural and intramural studies conducted. The section on the Geographic Information System describes the development of this new research tool. The Community Outreach/Relations section reviews activities that were undertaken to keep the community informed about and a part of the Project. The Future Directions section describes ancillary studies, and areas where NCI and NIEHS are now working to further epidemiologic investigations on environmental causes of breast cancer.

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Breast Cancer Statistics

Long Island, like other areas of the Northeast, has elevated rates of breast cancer.[1] The average annual age-adjusted breast cancer incidence rate for Nassau County increased from 104.4 (per 100,000 females) in 1981-1985 to 117.8 from 1992-1996 (13 percent change). The average annual age-adjusted mortality rate decreased from 35.3 in 1981-1985 to 30.6 in 1992-1996 (13 percent change). For Suffolk County, the incidence rate for female breast cancer increased from 92.3 to 113.6 over the same period (23 percent change). The mortality rate decreased from 33.6 to 31.1 (7 percent change).

For Schoharie County, the incidence rate for female breast cancer decreased from 87.5 to 86.0 from 1981-1985 to 1992-1996 (2 percent change). The mortality rate decreased from 42.0 to 25.6 over the same period (39 percent change).

For purpose of comparison, the breast cancer incidence rate for New York State increased from 90.1 to 101.6 from 1981-1985 to 1992-1996 (13 percent change). The mortality rate decreased from 31.1 to 28.2 (9 percent). Mortality rates for New York State have historically been higher than rates for the nation. During this same time period, the breast cancer incidence rate for the United States (SEER areas) increased from 94.7 in 1981-1985 to 110.6 in 1992-1996 (17 percent change), while the mortality rate decreased from 27.0 in 1981-1985 to 25.4 in 1992-1996 (6 percent change).

The incidence rate for female breast cancer for Tolland County was 93.8 in 1981-1985 and 119.8 in 1992-1996 (28 percent change). The mortality rate for the cancer was 31.8 in 1981-1985 and 26.3 in 1992-1996 (17 percent change).

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Breast Cancer Epidemiology

Breast cancer is the most frequently diagnosed non-skin cancer among women in the United States. It is second only to lung cancer in cancer-related deaths. An estimated 182,800 new cases of breast cancer will be diagnosed in 2000, and about 40,800 women will die of the disease.[2]

Geographic variation in breast cancer rates has been well documented, both internationally and within the United States. (See Appendix D) Some of this variation may be explained by differences in the population distribution of known breast cancer risk factors. It is estimated that 40 to 50 percent of U.S. breast cancer cases are associated with established risk factors. [3] These risk factors include:

The reasons for the remaining cases of breast cancer are not understood, and thus, researchers have turned to possible environmental causes for answers. Although public concerns have focused on exposure to environmental hazards such as pesticides, landfills, industrial chemicals, and electromagnetic fields, to date the evidence linking them to breast cancer has been inconclusive. Other factors that are being investigated as probably associated with breast cancer risk include hormone replacement therapy, alcohol consumption, diets high in fat, radiation exposure, obesity in postmenopausal women, physical exercise (beneficial), and long-term breast feeding (protective).

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Background

Steps Taken

The first phase of the LIBCSP focused on establishing contacts with the community and other agencies, and locating sources of data and scientific expertise. As part of this process, in January 1994, NCI and NIEHS convened a meeting of representatives of the NCI-designated cancer centers at New York University to stimulate interest in undertaking the LIBCSP. Represented were researchers from the American Health Foundation, Columbia-Presbyterian Cancer Center, Memorial Sloan-Kettering Cancer Center, Albert Einstein College of Medicine, New York University Kaplan Cancer Center, and Cold Spring Harbor Laboratory. The group discussed ways in which their research expertise could be brought to bear on elucidating the problem of breast cancer on Long Island, and was encouraged to submit grant applications to the National Institutes of Health (NIH) through its scientific review process.

In the spring of 1994, NCI and NIEHS staff met with breast cancer advocates in Bethesda, Md., to discuss community input into the research and participation on the ad hoc Advisory Committee.

Ten research projects were funded through new grant awards or supplemental funding of existing grants: two case-control studies on Long Island (Columbia University, State University of New York (SUNY) at Stony Brook), a case-control study on Schoharie County (American Health Foundation), a case-control study on Tolland County (Yale University), Metropolitan New York Family Registry for Breast Cancer Families (Columbia University), breast cancer screening study (SUNY at Stony Brook), and three laboratory studies on the biology of and susceptibility to breast cancer (Albert Einstein College of Medicine, Cold Spring Harbor Laboratory, New York University). The aim was to take multiple scientific approaches to address the problem of breast cancer on Long Island. Hence, the laboratory studies, while they did not yield Long Island-specific results as had been hoped, have advanced our overall understanding of the cancer. The projects were funded in 1994 and 1995 for periods ranging from one to four years, with the larger case-control studies receiving extensions. The LIBCSP is an extramurally funded research program, but NCI intramural scientists also have conducted several investigations.

Over the years, new contacts have been made and relationships forged to continue to obtain and exchange information and expertise relevant to the Project, such as with federal, state, and local government groups, including the U.S. Environmental Protection Agency (EPA), U.S. Geological Survey (USGS), Agency for Toxic Substances and Disease Registry (ATSDR), U.S. Census Bureau, New York State Department of Health, Nassau and Suffolk county governments; research and medical institutions; private organizations; and breast cancer advocacy and other community groups. Many sources of expertise have been pursued, particularly with respect to development of the GIS where the application of this technology to study of the environment and cancer is largely uncharted.

Because the LIBCSP arose from concerns raised by Long Island women with breast cancer and their families and friends, NCI and NIEHS have had an active community relations program to keep residents informed about developments and provide opportunities for participation in the overall Project. Town meetings and workshops have been hosted, and presentations made to community groups. Web sites have also been established to provide information.

Also, NCI's Cancer Information Service (CIS), which offers information on cancer and cancer treatment via the toll free number 1-800-4-CANCER, has been helpful. The CIS has regional offices that serve the entire country. Long Island is covered by Memorial Sloan-Kettering Cancer Center, New York, which maintains a community outreach office on Long Island. The CIS staff help keep the community informed about LIBCSP developments and provide NCI staff information related to outreach. More detailed information on communications and community relations is provided in the Community Outreach/Relations section of this report.

An ad hoc Advisory Committee of extramural scientists and community members advises NCI and NIEHS on the Project, and meets annually or as needed. The committee comprises 9 scientists, 1 health communications expert, and 5 community members. (See Appendix E) In addition, each of the two Long Island case-control studies (Breast Cancer and the Environment on Long Island, by Columbia University, and EMF and Breast Cancer Study, by SUNY at Stony Brook), has an external advisory committee.

The LIBCSP is a complex research effort that has charted new ground in environmental epidemiology. The assessment of environmental exposures and determining their relationship with cancer is difficult. From the Project's beginning, it was clear that new technologies would need to be develop to enable scientists to measure and analyze certain exposures, such as airplane emissions exposure, and then determine their relevance to breast cancer. New biological markers of individuals' cumulative exposures over years were, and continue to be, needed. The LIBCSP investigators made progress in these areas and developed new environmental measurement and laboratory techniques, and explored new ways to study the relationship between the environment and breast cancer. However, much remains to be learned, and NCI and NIEHS have on-going programs to develop methods for accurate determination of chemical exposures, spanning 20-30 years of an individual's life, relevant to breast cancer development. The LIBCSP applied the best available science and technologies to investigate the environment and breast cancer and to advance research methods.

With respect to the GIS-H, the science of developing GISs as tools to study relationships between environmental factors and cancer is in its infancy and presents many challenges. To implement the GIS-H, a one-year feasibility study was conducted by Brookhaven National Laboratory, and a working group of university and federal government experts then assisted NCI to prepare a detailed Request for Proposals (RFP) to develop and implement the tool. In the spring of 1999, NCI awarded the contract for the GIS-H. GISs are powerful computer systems that can store, manipulate, analyze, and display the spatial (geographic location) relationships between dissimilar data types. The GIS-H will provide a tool to study potential relationships between the location of breast cancer cases and sources of pollution. GISs have been in development for more than 20 years, but only with recent advances in computer hardware, software, and increased availability of geo-coded health and environmental data (date tagged to specific location(s)) have they come into use in public health promotion. In early 2000, the Oversight Committee for the GIS-H was established. It comprises 12 scientists and 5 community members who convene four times per year in person or by conference call. (See Appendix F)

The lead NIH scientists responsible for implementing the LIBCSP are G. Iris Obrams, M.D., Ph.D., Associate Director of the Epidemiology and Genomics Research Program (EGRP), Division of Cancer Control and Population Sciences (DCCPS), NCI, and Gwen Collman, Ph.D., Scientific Program Director, Chemical Exposures and Molecular Biology Branch (CEMBB), Division of Extramural Research and Training (DERT), NIEHS. Ellen Heineman, Ph.D., of EGRP, is Project Officer for the GIS. Linda Anderson, M.P.A., of EGRP, is Director of Communications for the Project.

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Primary Agents Studied

The LIBCSP researchers focused their attention chiefly on 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT), or its metabolite dichloro-2,2-bis (p-chlorophenyl) ethylene (DDE), DDE; polychlorinated biphenyls (PCBs); polycyclic aromatic hydrocarbons (PAH); and electromagnetic fields (EMFs). At the time of the Project's beginning, preliminary studies suggested that these exposures might be associated with breast cancer causation, and laboratory methods existed, or could be developed, to determine exposures that may have occurred many years earlier, when breast cancer would have been developing. The limited number of biomarkers that provide evidence of past human exposures is a major problem in cancer epidemiology. Indicators do not exist for most past exposures. An exposure may clear the body in hours or in a day, without leaving evidence perceptible by current scientific methods. For cancer, which has a long latency, exposures that occurred long before diagnosis are key.

At the time the LIBCSP was launched, there were very few results from animal experiments or human studies at that time that pointed to likely research possibilities. Two preliminary reports of blood analyses in small groups of women had suggested that certain pesticides in the environment might increase the risk of breast cancer.[4,5] This observation seemed plausible due to earlier experimental, clinical, and epidemiologic data that associated hormones, particularly estrogen, with breast cancer risk, and some pesticide compounds were known to be chemically similar to hormones.

The suspected pesticides, classified as organochlorines, include DDT/DDE and PCBs. These chemicals are known as xeno-estrogens because they exert an estrogenic effect, though weak, on human tissue.[6] Because estrogenic activity is known to be associated with breast cancer risk, the focus on xeno-estrogens was thought to be a potential field of research that might yield conclusive results.

DDT use began in the United States in the 1940s and continued widely until 1972 when it was banned. Although no longer used in the United States, the compound takes many years to disappear from the environment. The concern with DDT and its metabolite DDE grew when it was learned that they persist in the blood and accumulate in the human body, specifically in adipose (fat) tissue. Numerous studies have shown that DDT accumulates in breast tissue and that infants are exposed to it during lactation.[7] It has not yet been determined whether DDT causes cancer in humans although DDT was classified by the International Agency for Research on Cancer (IARC) as "possibly carcinogenic" based on animal studies.[8]

PCBs are a group of more than 200 compounds, called congeners, that have been used widely as coolants and lubricants in transformers, capacitors, and other electrical equipment. Products containing PCBs are old fluorescent lighting fixtures, electrical appliances containing PCB capacitors, old microscope oil, and hydraulic fluids. The manufacture of PCBs stopped in the United States in 1977 because of evidence that they accumulate in the environment and cause harmful effects. Breast cancer risk from PCBs has been studied for more than 30 years, and the data have been inconclusive at best. PCBs are known to have estrogenic properties in humans, but the effects are weak.[5] Importantly, PCB congeners are classified as estrogenic, antiestrogenic, or neither based on data from numerous research studies.[9] This may explain, to some degree, why results of studies evaluating the effect of PCBs on breast cancer have been conflicting.

After the LIBCSP was underway, findings from other research emerged that suggested the organochlorine compound dieldrin may be associated with increased risk for breast cancer and poorer survival from the disease. [10,11] As a result, dieldrin was added to the analyses being conducted in the study titled Breast Cancer and the Environment on Long Island.

PAHs are a group of ubiquitous pollutants caused by incomplete combustion of various chemicals including diesel fuel and cigarette smoke. The critical step in carcinogenesis is the formation of DNA adducts. However, the relationship between adducts formed from environmental risk factors, such as smoking, and development of breast cancer has not yet been determined. Insights into the extent of damage and mechanism of initiation of carcinogenesis will help provide a more comprehensive understanding of breast cancer.

Electromagnetic fields (EMF) are the result of living in modern times. Wherever electricity is used, a relative magnetic and electric field is produced. This includes the household where appliances, CD players, televisions and radios, and the general wiring in the house all produce EMF. Of public concern is the EMF produced by high voltage transmission wires running through neighborhoods. Theoretically, EMF became a suspected carcinogen when animal experiments demonstrated EMF suppression of melatonin secretion.[12] Melatonin suppresses mammary tumorigenesis in rats and blocks estrogen-induced proliferation of human breast cancer cells in vitro. Therefore, it was reasoned, that decreased melatonin production might lead to increased risk of breast cancer.

Epidemiologic studies assessing the effect of EMF exposures in occupational settings and by histories of electric blanket use have been inconclusive.[13-16] The 1999 NIEHS Report on power-line frequency electric and magnetic fields presented a summary of the literature on breast cancer associations and noted the lack of evidence of any relationship.[17] The challenge of EMF research remains accurate assessment of total exposure, particularly since the general population is likely exposed, at low doses, to ubiquitous and multiple sources. Additionally, due to the highly technical and costly instrumentation required to obtain actual EMF measurements, no published epidemiologic study on breast cancer has yet directly determined total EMF exposure.

The LIBCSP also is investigating the role of established risk factors for breast cancer. Such information and examination will give a more detailed picture of the breast cancer situation in the study areas.

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Research

Extramural Research

Breast Cancer and the Environment on Long Island
Marilie Gammon, Ph.D., Columbia University, New York, NY
(now located at the University of North Carolina at Chapel Hill, N.C.)

The cornerstone of the LIBCSP, Breast Cancer and the Environment on Long Island is investigating whether certain environmental contaminants increase risk of breast cancer among women on Long Island. The primary aims are to determine if organochlorine pesticides, including DDT, PCBs, PAHs, and the pesticides chlordane and dieldrin are associated with risk for breast cancer among women on Long Island. (The study is also sometimes referred to as the Columbia case-control study or the LIBCSP itself.)

The investigation has been funded by a grant to Columbia University, NY, and is led by Dr. Marilie Gammon, who relocated to the University of North Carolina at Chapel Hill in 1999 where she continues to lead the study. The study is a collaborative effort involving numerous New York City and Long Island researchers. In this population-based study, all women in Nassau and Suffolk counties who were newly diagnosed with breast cancer during a one-year period that ended mid-1997 (cases) were invited to participate. A comparison group (controls) of women who did not have breast cancer were randomly selected from the two counties. Altogether about 1,500 cases and 1,500 controls participated. The study participants completed a questionnaire administered by interview in their homes, and provided pre- and post-treatment blood samples and urine samples. In addition, a random sample of participants who had resided in their homes for at least 15 years participated in a study in which house dust, tap water, and yard soil samples were collected (home study). About 340 cases and 340 controls participated in this component of the study.

Blood and urine samples from 400 of the cases with invasive cancer, 200 of the cases with in situ disease, and 400 of the controls were randomly selected from the study population and analyzed. Laboratory analyses were conducted to measure organochlorine pesticides, and PAH-DNA adducts in blood, and urinary markers of estrogen metabolism. For the home study, samples were assayed for pesticides and PAHs. The blood and urine samples of all African-American study participants were analyzed to increase data available for this group. Further, all African-American women participants who had lived in their homes for at least 15 years were invited to be part of the home study.

Statistical analyses of the questionnaire data are now in progress. These data will be coupled with the results of the laboratory analyses to assess the risk for breast cancer associated with organochlorine pesticides and PAHs. Findings addressing these two primary hypotheses are expected to be published in the year 2000.

In addition, the grant provided funds for a feasibility study to develop a geographic modeling system to estimate historical exposure of study participants to compounds/agents that were included in the research project. This work is led by Maureen Hatch, Ph.D., a Columbia University member of the research team, and one report has been published on it.[18]

Other published reports to date have focused on necessary methods development. They include papers on assessment of variation in DDE and PCB levels over time, comparison of serum and adipose tissue levels of chemical compounds, and identification of groups of similar PCBs by, for example, estrogenicity and immunotoxicity.[19,20]

In 1998, Dr. Gammon, Steven Stellman, Ph.D., of the American Health Foundation and principal investigator of a LIBCSP study, and colleagues published results of a systematic study of correlations between adipose tissue and serum levels of organochlorine compounds.[21] The analysis validated that either tissue or blood can be used to assess a woman's body burden of organochlorine compounds, a point that has sometimes been challenged. Further, the researchers say, they demonstrated that the "profile" of individual organochlorine compounds found in human tissue was similar to that found in animals, such as fish and birds trapped in wildlife, suggesting similar environmental sources of exposure.

Beginning in mid-2000, a series of papers are expected to be published that will address results of biomarker analyses, environmental samples, and interview data on environmental exposures and non-environmental exposures (e.g., pesticide use, diet, medications, medical irradiation).

The study maintains a dedicated telephone line for inquiries, 212-305-9392, periodically publishes a newsletter for study participants (see Appendix G), and has a Web site: http://cpmcnet.columbia.edu/dept/sph/epi/libc.

The case-control study had its own external advisory committee, which comprised scientists and one Long Island community member. It held its last meeting in 1999.

Electromagnetic Fields (EMF) and Breast Cancer Study
M. Cristina Leske, M.D., M.P.H.
State University of New York, Stony Brook, NY

Dr. Cristina Leske, of SUNY at Stony Brook, NY, and colleagues are conducting a population-based case-control study to determine if EMFs are associated with increased risk for breast cancer. The study population is a subgroup of the population that is participating in Dr. Gammon's study and who have lived in their current Long Island residence for at least 15 years. About 600 cases and 600 controls are participating. The researchers interviewed the women about their EMF exposure, and visited their homes to take EMF measurements. This study is one of a very few studies that have included actual measurements of EMFs inside the homes of women with breast cancer and of healthy controls.

Information on occupational and residential EMF exposures, including appliance use, was ascertained from all participants during a special in-home visit. EMF measurements included spot measurements, 24-hour measurements, and ground current test-load measurements. Graphs of the 24-hour measurements taken in two rooms of the home were provided to study participants on request. In addition, the power lines adjacent to the home were diagramed.

The analyses will evaluate the possible association between EMF and breast cancer, taking into account other known and suspected risk factors for breast cancer. The study has an external scientific advisory committee. The study's findings are expected to be reported in the year 2000 or 2001.

The researchers conducted a pilot study comparing methods for assessing residential exposures to EMFs, which was useful in determining the methods they used. This pilot research is described in a published paper.[22]

Epidemiology of Breast Cancer and Serum Organochlorine and
Serum Organochlorine Compounds and Breast Cancer on Long Island

Steven D. Stellman, Ph.D., American Health Foundation, New York, NY

Dr. Stellman and colleagues are conducting a hospital-based case-control study to investigate risk for breast cancer in relation to levels of organochlorine compounds, such as DDT and PCBs. Women were recruited for the study who were being treated at North Shore University Hospital, Manhasset; Long Island Jewish Medical Center, New Hyde Park; and Bassett HealthCare, Inc., which serves Schoharie County. About half of the women who participated in the North Shore University Hospital/Long Island Jewish Medical Center component of the study were residents of Long Island. Both blood serum and adipose tissue were obtained from the study participants.

In the North Shore University Hospital/Long Island Jewish Medical Center study component, the researchers collected breast tissue samples from 360 women who were treated for invasive or in situ breast cancer (cases), and 670 women who had surgery for benign breast disease or other non-breast cancer conditions (controls). The women were treated between 1994 and 1996. Preliminary findings suggest that neither DDE or total PCB exposure was associated with increased risk for breast cancer. Dr. Stellman expects to publish findings on these and other chemical analyses in the year 2000.

In addition, the researchers are conducting medical follow-ups on the cases to determine whether survival or recurrence of breast cancer may be related to body burden of organochlorine compounds.

In early 1999, a questionnaire was mailed to the cases in order to obtain data on lifestyle changes and other patient characteristics that may have changed since the women were diagnosed with breast cancer. The women were also asked to provide new blood samples to permit study of changes in organochlorine compound levels over time.

In the Schoharie County component of the study, 36 women who were diagnosed with invasive or in situ breast cancer between 1995 and 1997, and 56 women who had benign breast disease or other non-breast cancer conditions participated. Blood serum and adipose (fatty) tissue were obtained. This population is too small to permit detailed analysis. When results from the Long Island and Connecticut study populations are available, though, it will be possible to look for differences in risk for breast cancer that may be associated with body burden levels of chemicals.

As part of the study, Dr. Stellman conducted an analysis which demonstrated that either adipose tissue or serum could be used to assess body burden levels of organochlorine compounds and PCBs.[23]

Organochlorine Compounds and Risk of Breast Cancer
Tongzhang Zheng, M.D., Sc.D., Yale University, New Haven, CT

Dr. Tongzhang Zheng, of Yale University, New Haven, CT, and colleagues have been conducting a hospital-based case-control study in Connecticut to investigate risk for breast cancer associated with exposure to organochlorine compounds. Levels of organochlorine compounds are being measured in breast adipose (fatty) tissue and blood serum obtained from women who had surgery or biopsies for breast cancer or benign breast disease. The organochlorine compounds examined are: hexachlorobenzene (HCB), a byproduct of the manufacture of chemicals used as solvents, other chlorine-containing compounds, and pesticides; β-benzene hexachloride (β-BHC), an insecticide; PCBs; and DDT/DDE. Study participants also provided medical and diet histories, and information on alcohol use, cigarette smoking, and other environmental exposures.

The overall study is considered Long Island Breast Cancer Study Project (LIBCSP)-related because of its potential relevance. As an adjunct to the study, the researchers conducted a pilot case-control study focusing on Tolland County, CT. For this population, blood serum and the same types of medical, lifestyle, and risk factor information were collected as for the Connecticut study.

Four reports have been published on findings from the Connecticut study. The researchers did not find an increased risk for breast cancer associated with exposure to either HCB, BHC, DDT/DDE, or PCBs.[24-27] The analyses included 304 women who had breast cancer (cases), and 186 women who had benign breast disease (controls) who were treated at Yale-New Haven Hospital between 1994 and 1997 and who were ages 40-79.

The number of women diagnosed with breast cancer in Tolland County were too few to conduct a detailed analysis (155 cases and 180 controls). Researchers will compare body burden levels of chemical agents across study populations and look for possible associated differences in risk when the case-control studies conducted at Columbia University and the American Health Foundation (which includes Schoharie County) are completed.

Reducing Barriers to Use of Breast Cancer Screening
Dorothy S. Lane, M.D., Ph.D., State University of New York at Stony Brook, NY

Dr. Dorothy Lane, of SUNY at Stony Brook, NY, is investigating 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. Implementation of the interventions and the post-intervention surveys of the women and physicians are now completed. The pre- and post-intervention comparative data analysis is underway to evaluate the efficacy of the interventions.

In a first step of the study, Dr. Lane and colleagues surveyed more than 8,900 Long Island women, ages 50-80, by telephone about their use of breast cancer screening, and over 540 doctors by questionnaire.[28-30] The researchers identified over 3,400 women who had not received mammograms in the past two years and the past two years prior to that. Forty-five percent of women in the 65 years-of-age and older age group were found to underuse mammography, and 34 percent of women in the 50 to 64 years-of-age group to underuse it. The chief reasons given for not getting mammograms were procrastination and not believing a mammography was needed - the latter reason given more frequently by women in the older age group. The researchers found that over 80 percent of the women who were underusers of mammography had less than a college degree, the majority (58 percent) had family incomes of under $35,000, and most were homemakers or were retired.

During the intervention phase of the study, the effectiveness of telephone counseling and physician education were tested. The first step in the telephone counseling intervention was an annual mailing which both alerted women that they would be called by the Early Detection Guidelines Education (EDGE) Project and encouraged them to go for mammography. Three annual mailings were conducted during the intervention period and included educational materials and incentives to promote screening. A three-month period elapsed following each educational mailing before initiating telephone counseling of women who did not return the response sheet, in order to allow them time to obtain a mammogram if they were prompted by the mailings. In the intervention group, 1,165 underuser women reported that 597 mammograms were obtained during the first year of the intervention, and 615 mammograms were obtained during the second year of intervention, for a total of 1,195 mammograms. The post-intervention women's survey is currently being analyzed and will provide additional outcome data.

A quality control evaluation was also conducted of a sample of 117 counseling calls for the telephone counseling intervention. Seventy-one percent of women who were contacted reported that the calls were "entirely reassuring," and 71 percent of the women said the calls were "entirely helpful." In addition, 65 percent of the women said that they felt "entirely encouraged" by the EDGE counselor to have mammogram in the future. Among women who mentioned a barrier to mammography, 64 percent reported that after discussing it with the EDGE telephone counselor, the barrier would not keep them from getting a mammogram in the future.

Ninety-three physicians obtained the in-office continuing medical education intervention which included three modules: (1) office systems, (2) behavioral counseling, and (3) revisiting physical examination of the breast. The in-office intervention also included an optional follow-up visit with the office staff and a subsequent visit by a standardized patient. The standardized patient simulated a patient with a specific set of characteristics and provides feedback to the physician about his or her counseling and examination techniques from a patient's perspective. Seventy-eight office staff visits were made, and 63 standardized patient visits.

As an adjunct to the educator office visit, Dr. Lane and colleagues developed a loose-leaf workbook that can also be used as a freestanding self-instructional Continuing Medical Education (CME) activity. The workbook was mailed to those physicians in the intervention group who did not receive an in-office visit. Physicians' anonymous evaluations of the in-office intervention were very positive. Analysis of the post-intervention physicians' survey is currently underway and will permit comparisons to baseline physician breast cancer screening data.

Findings from the study are expected to be reported in the year 2000.

Environmental Exposures and Breast Cancer on Long Island
Erin O'Leary, Ph.D., State University of New York at Stony Brook, NY

In this study of environmental exposures and breast cancer, Dr. Erin O'Leary, of SUNY at Stony Brook, NY, is conducting an exploratory investigation to determine whether length of residence in close proximity to hazardous waste sites, industrial sites, 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.

The study population was selected from a cohort of New York State residents in 1980 who had lived at least 18 years in their current residences and had completed a mail questionnaire. Within the cohort, 3,097 women from Long Island answered the questionnaire. From this Long Island group, data on 105 women who had been diagnosed with breast cancer (cases) as of 1992 were compared to data on 210 randomly selected Long Island women who had not had breast cancer (controls).

Data on each woman's residence was linked with data on environmental exposures to pesticides, solvents, and metals. This doctoral research is being conducting under the guidance of dissertation committee members John Vena, Ph.D., Jo Freudenheim, Ph.D., and others of the State University of New York at Buffalo, where Dr. O'Leary was previously located.

Findings will be reported in the year 2000.

Metropolitan New York Registry of Breast Cancer Families
Ruby T. Senie, Ph.D., Columbia University, New York, NY

The Metropolitan New York Registry for families with a history of breast or ovarian cancer invites families who have a history of either or both of these cancers to participate. The Registry is one of six sites funded by NCI to establish a major resource of data and biospecimens from high-risk families to be used for research purposes. This readily available research resource will help speed research on the causes of breast and ovarian cancer, familial susceptibility, and the impact of environment and lifestyle on their development.

The New York Registry, directed by Dr. Ruby Senie, is based at Columbia University, NY, and includes five collaborating area medical centers: Stony Brook University Hospital and Medical Center, Mt. Sinai Medical Center, New York University Medical Center, Beth Israel Medical Center, and Memorial Sloan-Kettering Cancer Center. Individuals who are interested in learning more about the Registry or in enrolling are welcome to call 1-888-METRO-08. On Long Island, individuals may enroll through Stony Brook University Hospital and Medical Center by calling 1-800-867-3561. Information on the Registry is also available from its Web site: http://www.metronyregistry.org.

The Registry seeks the participation of family members both with and without a history of cancer. Both males and females are needed for proposed studies. Participants are asked to contribute personal health information, blood, and urine samples. All information is kept confidential, and all data and specimens have identifying information removed. As of November 1999, 1,105 families, including 3,092 men and women, have enrolled in the Registry, and the number continues to steadily increase. Additional family members are being asked to join because most of the ongoing Registry-supported studies require genetic analyses from three or more relatives.

A component of the Registry offers genetic counseling and testing for three BRCA1 and BRCA2 mutations for any interested families of Ashkenazi descent. These three mutations have been associated with increased risk for breast and ovarian cancers. Those Registry members who wish to know if they carry one of these mutations use the information to guide their decisions about screening and options for disease prevention.

Recruitment to the Registry began in January 1997. The Registry has reached its goal for numbers of families enrolled, but it still needs more relatives per family and more families of African-American and Hispanic heritage to participate.

Several research projects are now underway using Registry resources. See Future Directions section.

Estrogen Metabolites as Biomarkers for Breast Cancer Risk
(also known as Breast Cancer Risk and Inducibility of P450s)
H. Leon Bradlow, Ph.D., Strang Cancer Prevention Laboratory, New York, NY

Long Island investigators investigated 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 -hydroxyestrone. Earlier studies suggested that the balance between the estrogen metabolite 16 -hydroxyestrone, which has been associated with breast cancer, and 2-hydroxyestrone, which has not, may affect risk for the disease. Dr. H. Leon Bradlow, of Strang Cancer Research Laboratory, New York, NY, and Geoffrey Kabat, Ph.D., of SUNY at Stony Brook, examined the ratio between the two metabolites in urine.[31] They 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 research is needed to confirm the findings, and the researchers are now conducting another investigation. See Future Directions section.

Regulation of Scatter Factor Expression in Breast Cancer
Eliot M. Rosen, M.D., Ph.D., Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, NY

Dr. Eliot Rosen and colleagues, of Albert Einstein College of Medicine, New Hyde Park, NY, evaluated how scatter factor, a growth factor, may regulate the growth of human breast cancers.[32] Greater knowledge of the mechanisms important for breast cancer development and progression is of keen scientific interest. Such information can provide insights to better understand the nature of the disease and to develop new therapies to prevent or halt its progression.

Most human breast cancer cells contain high levels of the receptor for scatter factor, which means that, in the laboratory, breast cancer cells will vigorously multiply in the presence of the growth factor. Dr. Rosen and his colleagues found that scatter factor causes human breast cancer cells to move faster and to be more invasive in cell cultures. The growth factor induces the breast cells to produce an enzyme that degrades tissue, they found, thus facilitating tumor invasion.

In laboratory animals, they found that scatter factor greatly stimulates the formation of new blood vessels (angiogenesis), an essential step for tumor growth and spread (metastasis). They also found that invasive breast cancer tissue samples with higher levels of scatter factor have higher levels of von Willebrand factor (VWF), which is a protein produced by the lining of blood vessels. This suggests that higher levels of VWF may be associated with greater angiogenesis.

In other experiments, the researchers found that levels of scatter factor were significantly higher in invasive breast cancer tissue than in benign breast lesions or non-invasive breast cancers (ductal carcinoma in situ (DCIS)). Invasive breast cancers had nearly four times the scatter factor content of DCIS tissue. And tumors that had spread to the axillary lymph nodes had higher levels of scatter factor than invasive cancers that had not yet spread beyond the breast, although this difference was not as great as that seen between invasive breast cancers and DCIS tissue. Scatter factor levels did not vary by histologic (cell) type of invasive breast cancer.

Dr. Rosen and his colleagues also demonstrated in an animal model that scatter factor can stimulate the growth of human breast tumors. Human breast cancer cells altered so that they produced high levels of scatter factor were injected into mice. The researchers found that mammary (breast) tumors grew much more rapidly in these mice than in those that received unaltered breast cancer cells.

Tissue specimens from the Long Island Jewish Frozen Tumor Bank at Long Island Jewish Medical Center were used for the research. Findings were reported in 1996. Since this LIBCSP-supported study, Dr. Rosen has continued his research on scatter factor further advancing understanding of its role in tumor development.

RDA Analysis of Breast Cancer
Michael H. Wigler, Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

Dr. Michael Wigler, of Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, has been examining genetic changes in breast tumor tissue from patients on Long Island using a technique called representational difference analysis (RDA). In a pilot study, he demonstrated that the technique permits cloning of DNA probes that mark the presence of genetic lesions in tumors. Advances in the development of this technique as a research tool are of interest because, among other reasons, certain point mutations in genes may be linked to environmental exposures and may be characteristic of specific environmental exposures.[33] The seed money provided through the LIBCSP for this pilot research was the foundation for a larger research effort subsequently funded by the U.S. Department of Defense (DOD).

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Intramural Research

New Statistical Methodology for Determining Cancer Clusters
Martin Kulldorff, Ph.D., National Cancer Institute, Bethesda, Md.
(now at the University of Connecticut Health Center, Farmington, CT)

Dr. Martin Kulldorff, while at NCI, and colleagues developed an innovative statistical technique that shows that women living in a broad stretch of the metropolitan northeastern United States, which includes Long Island, are slightly more likely to die from breast cancer than women in other parts of the Northeast.[34] The study does not explain why these women are at higher risk of death, and the researchers note that the increase may be due to differences in well-established risk factors for breast cancer which they were unable to include in the analysis. The breast cancer mortality rate along a section of the East Coast stretching from New York City to Philadelphia was 7 percent higher than the rest of the Northeast. The study was descriptive and did not include risk factors in the analysis.

Geographic Influences on Women's Health
Susan R. Sturgeon, Dr.P.H., National Cancer Institute, Bethesda, Md.
(now at the University of Massachusetts, Amherst, Mass.)

Dr. Susan Sturgeon is conducting a study to determine if regional differences in the prevalence of established or suspected risk factors for breast cancer, and certain hypothesized environmental risk factors may explain geographic variations in death rates for the disease. She began the research at NCI and is now continuing it from the University of Massachusetts, Amherst, Mass.

The study focuses chiefly on geographic variations among white women in the Northeast and South - where differences in breast cancer death rates are most pronounced, and on rural and urban variations in rates in these regions. A component of the study also surveyed women from Nassau County, NY, a densely populated area with historically elevated breast cancer death rates.

Breast cancer death rates for white women vary substantially by region of the country and population density. Rates for women in the Northeast are 32 percent higher than in the South, which has the lowest rates. Furthermore, rates tend to be higher in urban than rural areas within the same regions of the country. They can also vary within counties with similar population densities and within the same region. Breast cancer death rates for black women do not differ as markedly by geographic area as for white women, and for this reason, an analysis focusing on geographic variations would not be informative. The researchers did include black women in the data collection, however.

The study focuses on 3,800 white women, 25 years-of-age or older (selected by random digit dialing). Dr. Sturgeon and colleagues interviewed the women by telephone for information about their age, menstrual and reproductive history, personal and family history of breast cancer, history of benign breast biopsies, exogenous estrogen use, body mass index, dietary fat intake, and alcohol consumption. Information was also obtained on the women's exposure to pesticides and other chemicals, automobile exhaust, sources of drinking water, and the proximity of their residences to landfills, airports, and factories. Similar information was collected on about 620 black women. About 300 white women from Nassau County were included in the study population.

The Northeast area covered in the study includes Connecticut, Delaware, Maine, Maryland, Massachusetts, New Jersey, New Hampshire, New York, Pennsylvania, Rhode Island, Vermont, and the District of Columbia. The southern states are Alabama, Arkansas, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, and West Virginia.

The findings are expected to be published in late 2000 or 2001.

The current study is a follow-up to a 1995 analysis by Dr. Sturgeon and colleagues of geographic differences in breast cancer death rates that demonstrated that the mortality risk for breast cancer among white women is similar in the Northeast, Midwest, and West, after recognized risk factors for the disease are taken into account.[3] Moreover, the differences between these regions and the South narrowed after accounting for such factors. The study did not explain all the regional differences in breast cancer, but provided perspective and laid the groundwork for the present study.

New York State Cancer Registration Project
Brenda Edwards, Ph.D.
National Cancer Institute, Bethesda, Md.

Dr. Brenda Edwards, Associate Director of the Surveillance Research Program, NCI, worked with the New York State Department of Health and Long Island cancer registrars to review state cancer registration and reporting procedures for breast cancer. She conducted a study of medical records of breast cancer cases on Long Island, and looked at the accuracy of reported stage of diagnosis for female residents using New York Cancer Registry and a report from the Centers for Disease Control and Prevention (CDC) on data from 1978-1982, which indicated a high percentage (18 percent) of distant disease for Long Island. A 10 percent oversample was used to obtain 100 cases per year per county to reach a total of 600 cases. For 1989-1991 in Long Island, the stage distribution showed a smaller percentage of metastatic disease (7 percent) than in the older reported data (18 percent for 1978-1982). When comparing data reported to New York State to U.S. data, overall agreement was good (73 percent); however, misclassification was found at all stages and in both directions (i.e., upstaging and downstaging). The final adjusted stage distribution for 1989 and 1991 showed there was somewhat more regional disease in Long Island than was found in national data among white women.

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Geographic Information System for Health

In May 1999, NCI awarded a contract to AverStar, Inc., of Vienna, Va., to develop and implement the GIS-H for breast cancer studies on Long Island. The contract award was for $4,872,309 for Phase 1 (two years) and Phase 2 (three option years). Phase I is to develop and deliver the system, and Phase 2 is for system maintenance and data expansion to respond to research needs.[35] (See Appendix H)

The GIS-H data layers will include geographic data for general mapping purposes and demographic data. Data on health care facilities, health care surveys, breast cancer, and the environment will also be included. The environmental data will include information on contaminated drinking water; sources of indoor and ambient air pollution, including emissions from aircraft; EMFs; pesticides and other toxic chemicals; hazardous and municipal waste; and radiation. The system will rely chiefly on existing databases obtained from federal, state, and local governments, and private sources, with emphasis placed on high-quality data. Initially, about 50 databases are slated to be in the system.

In October 1999, Long Island residents were invited to contribute information on environmental exposures that may not be in existing databases at a series of town meetings on Long Island. Some of the data to be included in the GIS-H are publicly available, but other data are confidential or proprietary, such as medical records. As a result, various levels of access to the GIS-H will be established to safeguard data while maximizing the system's usefulness as a research tool. This will ensure that individual records remain confidential.

Use and access to the system will be guided by an Oversight Committee which meets for the first time in March 2000. The 17-member committee is made up of members of the established ad hoc Advisory Committee to the LIBCSP, as well as federal, state, and local government specialists; external consultants; and additional representation from the Long Island community. The committee will advise NCI on policies and procedures, review the system's operations, and review and approve research proposals from investigators to use the GIS-H. The system is to be ready for researchers to use in pilot studies in mid-2001. Dr. Heineman, project officer, has begun acquainting the research community with the system through presentations at scientific meetings and writings.

A Web site is available where the public and researchers can follow the GIS-H's progress and obtain summary information about the databases: http://li-gis.cancer.gov. See Community Outreach/Relations section for further information.

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Other studies on breast cancer that may contribute to understanding the reasons for breast cancer on Long Island are monitored for their potential relevance. Chief among them are five of the research projects that make up the Northeast and Mid-Atlantic Breast Cancer (NE/MA) Study, including the study by Dr. Zheng that is described in the Research section. These studies found no significantly increased risk of breast cancer associated with breast adipose tissue levels of PCBs or organochlorine pesticides, including DDT, DDE, trans-nonachlor, oxychlordane, b-BHC, and HBC. Further, assessment of the joint effects for DDE and PCBs did not show a significant interaction between the two factors on the risk of female breast cancer. The researchers also did not find a significant association between breast cancer risk and serum levels of PCBs or organochlorine pesticides. None of the NE/MA research projects on chemical exposures focused on women in geographic areas covered by in the LIBCSP; thus, findings from the Project continue to be of great interest.

A report on the NE/MA Study is being submitted to Congress in 2000. The studies of interest and their principal investigators are: "Environmental and Genetic Determinants of Breast Cancer," Jo Freudenheim, Ph.D., SUNY at Buffalo, NY; "Environmental Factors and Breast Cancer Risk in Maryland," Kathy Helzlsouer, M.D., Johns Hopkins University, Baltimore, Md.; "Environmental and Genetic Determinants of Breast Cancer," Mary Wolff, Ph.D., Mt. Sinai School of Medicine, New York, NY; and "Organochlorine Compounds and Risk of Breast Cancer," Tongzhang Zheng, M.D., Sc.D., Yale University.

David Savitz, Ph.D., of the University of North Carolina at Chapel Hill, N.C., is conducting two population-based case-control studies in North Carolina on breast cancer and the environment. One study is exploring a variety of possible risk factors, including environmental factors such as EMF occupational exposures, ionizing radiation and other exposures of health care workers, and the other study focuses on pesticides. Dr. Savitz's research is of particular interest because of the large African-American population in the 24-county study area that permits separate analysis of data on this group. On Long Island, the African-American population is not large enough to permit the Columbia case-control study to conduct separate analysis on this group. Special efforts were made, however, to maximize the amount of information collected on African Americans in the LIBCSP so that the participants can be well described.

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Community Outreach/Relations

NCI, NIEHS, and the LIBCSP investigators have undertaken many different types of activities to keep concerned members of the community, governmental entities, medical and research institutions and private organizations informed about the LIBCSP and involved in its activities.

NCI and NIEHS staff have traveled to Long Island on numerous occasions to give presentations and meet with groups. Periodic "Updates" have been issued. (See Appendix I) Also, a Web site provides extensive information about the Project, and a separate, but linked, Web site is available on the GIS-H (LIBCSP Web site: http://cancercontrol.cancer.gov/LIBCSP; and GIS Web site: http://li-gis.cancer.gov).

A variety of public programs have been hosted. In 1995, a town meeting was held to discuss breast cancer on Long Island and to report on the start of the LIBCSP studies. Meetings of the ad hoc Advisory Committee to the LIBCSP, which are open to the public and take place in the Long Island/New York area, were held in 1995, 1996, and 1997. Another meeting is planned for the year 2000. Typically about 100 community members and scientists attend. For the GIS-H, three workshops were held for the community and one workshop was held for LIBCSP investigators in 1996 to obtain their input on development of the Request for Proposals (RFP) to develop the research tool. Following the award of the contract for the GIS-H, in the fall of 1999, a series of seven town meetings were hosted in four locations on Long Island to obtain information from residents about sources of environmental pollution that may not be in existing records. Members of the Long Island Breast Cancer Network (LIBCN), a coalition of Long Island breast cancer groups, helped to plan the publicity and sites for the town meetings and to promote them. Individuals may continue to contribute information through the GIS-H Web site, or by writing to: LIBCSP-GIS c/o NOVA Research Company, 4600 East-West Highway, Suite 700, Bethesda, Md. 20814-3415.

NCI staff, as well as some of the scientists who are conducting the LIBCSP studies, regularly report on the Project at meetings of the LIBCN, which are held on Long Island every other month.

The ad hoc Advisory Committee to the LIBCSP includes five community members (Ms. Francine Kritchek, Ms. Dee McCabe, Ms. Karen Miller, Ms. Carolyn Thompson Taylor, Ms. Victoria White). The community representatives established an investigator liaison program in which a community member was assigned to each of the LIBCSP studies to follow their progress. The Oversight Committee for the GIS-H includes five community members (Ms. Barbara Balaban, Ms. Karen Miller, Ms. Sarah Meyland, Ms. Martha Rogers, and Ms. Victoria White).

Dr. Gammon and other members of the Breast Cancer and the Environment on Long Island investigative team have made many detailed presentations to community and health professional groups to publicize the opportunity for eligible Long Island women to participate in the case-control study, as well as to give progress reports. The study maintains a dedicated telephone line for inquiries, periodically publishes a newsletter for study participants, and has a Web site (telephone: 212-305-9392; Web site: http://cpmcnet.columbia.edu/dept/sph/epi/libc). The external advisory committee for the case-control study included a Long Island community member (Ms. Barbara Balaban). Dr. Gammon also has sought the advice and assistance of members of the LIBCN in outreach efforts. Breast cancer advocates also provided funds for Dr. Gammon to conduct an analysis of Long Island women diagnosed with DCIS during the same time period as the Columbia case-control study.

Dr. Leske formed a community advisory group to provide a liaison between her EMF and breast cancer study and the community. The advisors meet regularly with the research team and have contributed to the study's educational and community aspects (Ms. Mary Dowden, Ms. Miriam Goodman, Ms. Mary Joan Shea). They also secured funds from breast cancer advocacy groups to enable the researchers to purchase additional EMF meters to speed their work.

The New York Metropolitan Registry for Breast Cancer Families has a special toll free number that Long Island residents may call to inquire about enrolling in the Registry (1-800-867-3561). Stony Brook University Hospital and Medical Center is a collaborating institution and provides a location on Long Island where individuals may go to learn about the Registry and enroll. Dr. Senie and her team give many presentations to publicize the opportunity for eligible families to enroll. The Registry also publishes a newsletter and has a Web site (http://www.ccc.columbia.edu/metro.html). The Registry has a consumer representative on its advisory group.

Community members submitted a list of chemicals of interest to them as possible breast carcinogens. EPA, NIEHS, and IARC provided information from their various databases on carcinogenicity and toxicology to help assemble summary information about the chemicals. Ruth Allen, Ph.D., of EPA, while on a detail to NCI and on a continuing basis after she returned to her agency, led the effort to develop the summary tables. (See Appendix K) EPA's Richard Hill, M.D., Ph.D., Science Advisor, Office of Prevention, Pesticides and Toxic Substances, facilitated acquisition of the various databases. Reviews of the list of chemicals indicated that the majority of them are being tested for in the LIBCSP, in either drinking water, soil, dust, or in blood samples. Dr. Allen coordinated one review and made copies available of the summary tables on computer disk to community members, and has met with them periodically to explain the project. Dr. Gammon also conducted a review and discussed it with community members. A member of the LIBCN serves as the liaison with interested community members (Ms. Elsa Ford).

NCI and NIEHS will continue to keep interested members of the public and researchers informed about the results of LIBCSP as they are published and as the GIS-H is developed.

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Future Directions

Dr. Gammon submitted a grant application to NIH proposing to follow the women who participated in Breast Cancer and the Environment on Long Island to see if there is a relationship between exposure to organochlorine compounds and survival from breast cancer.

In addition, ancillary studies from Dr. Gammon's case-control study which draw upon the same population have been initiated. She is conducting immunohistochemical detection of p53 protein in tumor tissue (DOD funded). Habibul Ahsan, M.D., of Columbia University, and colleagues are examining whether certain polymorphic variants in genes involved in the biosynthesis and metabolism of estrogen and environmental carcinogens are associated with risk for breast cancer (DOD, NCI, and Cancer Research Foundation of America funded). A study, by Sharon Hayes, M.Phil., and Regina Santella, Ph.D., of Columbia University, is using a different assay (an immunoflourescent detection method) than was used in the Columbia case-control study (ELISA) to analyze PAH-DNA adducts in the etiology of breast cancer (DOD and NCI funded). Ainsley Weston, Ph.D., of the Centers for Disease Control and Prevention (CDC), is analyzing p53 haplotypes in blood, and Paul Brandt-Rauf, M.D., Ph.D., Dr.P.H., is analyzing p53 antibodies in blood (Oncogene Science funded).

Dr. Bradlow and Dr. Kabat are expanding on their LIBCSP research on estrogen metabolites in urine as biomarkers for risk for breast cancer (see Research section). This study, led by Dr. Kabat, is investigating whether the ratio of 2-hydroxyestrone/16 -hydroxyestrone is lower in families with a stronger inherited pattern of breast cancer risk compared to families with a weaker pattern, and in paired sisters who differ by their breast cancer status. The researchers are using biospecimens from women who are participating in the New York Metropolitan Registry for Breast Cancer Families. The research began in 1998 and is funded by the Registry.

Much remains to be learned in order to achieve scientifically credible and realistic assessments of environmental exposure and health risks. To further research in this area, NIEHS, in collaboration with NCI, NIH, and other federal agencies, sponsored the workshop "The Role of Human Exposure Assessment in the Prevention of Environmental Diseases" in Rockville, Md., in the fall of 1999. The 3-day meeting focused on the exposure-dose-response paradigm and current opportunities and challenges in exposure assessment research. Based on the scientific input received at the meeting, NCI and NIEHS plan to issue a Request for Applications (RFA) in the year 2000 to stimulate research in the field.

In response to an RFA, in 1999, NCI and NIEHS funded five investigations to explore reasons for regional variations in breast cancer rates in the United States:

In the area of GIS development, NCI will issue a Program Announcement (PA) in the year 2000 to encourage investigators to submit proposals for studies to refine GIS and related methodologies, and use the technology for cancer research. The PA will facilitate collaboration among researchers to promote development of GIS methodology; foster appropriate use of GIS for epidemiologic, behavioral, and cancer surveillance research; and facilitate integration of types and levels of data in program planning, implementation, and evaluation.

While great strides have been made, particularly in molecular biology and genetics, toward understanding breast cancer as a disease, a particularly desired goal is to alter its incidence and mortality. Screening and prevention programs nationwide are committed to this goal and have already begun to make an impact. Breast cancer death rates in the United States have been decreasing about 2 percent per year since 1990, while occurrence has not substantially changed. Identification of modifiable risk factors offers the greatest opportunity to change incidence rates.

The question of whether any environmental factors (e.g., substances present outside of the body, including diet-related components, and alcohol) are associated with risk has been pursued by many investigators with the hope of developing prevention strategies. Human population studies that plan to assess multiple factors together, such as cancer genes, environmental exposures, lifestyle, and behavioral characteristics, require large numbers of study participants and biologic specimens for quantifying exposures. This endeavor may necessitate forming investigator networks and developing new strategies to collaborate in jointly ascertaining study populations and establishing shared infrastructures and specimen repositories. Much interest has been generated regarding genetic determinants (genotypes) of enzymes that metabolize environmental chemicals or endogenous hormones in the body. Increased risk of breast cancer associated with specific genetic polymorphisms requires confirmation, and studies of ethnically diverse groups with differing breast cancer rates may be especially enlightening. Laboratory research has demonstrated that breast tissue in certain time periods of development, particularly related to endogenous hormones (mainly estrogens), is more susceptible to the effect of carcinogens. Particular attention to timing of environmental exposures, e.g., during prenatal, adolescent, reproductive, and postmenopausal periods when hormonal activity may increase breast tissue susceptibility, could lead to new insight into the pathogenesis of breast cancer. Setting priorities for conducting epidemiologic studies will be facilitated by future basic research that characterizes the biological effects of environmental chemicals, particularly those that may have estrogenic activity such as endocrine disruptors, and developing models to determine what influences body burden of suspected carcinogens, e.g., persistent pesticides in the food chain. In addition, a major challenge for breast cancer epidemiologists is to develop methods for accurate determination of chemical exposures, spanning 20-30 years of an individual's life, relevant to breast cancer development.

Due to the complexity of these questions and of breast cancer itself, it is not expected that any one group of studies, research approach, or scientific discipline will be able to singly provide an answer.

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